TWI334416B - Gyrase inhibitors and uses thereof - Google Patents

Gyrase inhibitors and uses thereof Download PDF

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TWI334416B
TWI334416B TW093102200A TW93102200A TWI334416B TW I334416 B TWI334416 B TW I334416B TW 093102200 A TW093102200 A TW 093102200A TW 93102200 A TW93102200 A TW 93102200A TW I334416 B TWI334416 B TW I334416B
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Paul S Charifson
David D Deininger
Anne-Laure Grillot
Yusheng Liao
Steven M Ronkin
Dean Stamos
Emanuele Perola
Tiansheng Wang
Arnaud Letiran
Joseph Drumm
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Vertex Pharma
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Description

1334416 玖、發明說明： 【發明所屬之技術領域】 本發明係有關醫藥化學的領域及有關抑制細菌促旋酶和 Τορο IV之化合物，及其醫藥組合物。該等化合物可作為細 菌促旋酶和Τορο IV活性的抑制劑的使用。本發明也有關治 療哺乳動物細菌感染之方法和有關減少生物樣品中的細菌 量之方法。 【先前技術】 長久以來已認出抗生素的細菌，且在今天其被認為是嚴 重的全世界性健康問題。抗藥性的結果，一些細菌感染以 抗生素治療是困難的或甚至不能治療。這個問題因在某些 細囷株例如肺炎雙球菌（streptococcus pneumoniae)(SP)、結核 分枝桿菌（Mycobacterium tuberculosis)和腸球菌中最近已發 展多重抗藥性而變得特別嚴重。抗萬古黴素之腸球菌的出 現特別地引起恐慌，因為萬古黴素為從前用於治療此感染 之唯一有效的抗生素，和已被認為是許多感染之"最後手段" 之藥物。而許多其他抗藥性細菌不會引起威脅生命之疾 病’例如腸球菌，擔心其會誘發抗藥性之基因流傳到其中 抗曱氧西林（Methicillin)性已普遍之更致命的生物例如金黃 色葡萄球菌（De Clerq，等人，Current Opinion in Anti-infective Investigational Drugs, 1999, 1, 1; Levy, "The Challenge of Antibiotic Resistance"，科學美國（Scientific American)，1998 年三月）。 另外所關切的是抗生素性如何很快地流傳。例如，直到 1960年代SP全世界性地對青黴素敏感，和在1987中只有1334416 发明Invention Description: TECHNICAL FIELD The present invention relates to the field of medical chemistry and to compounds for inhibiting bacterial gyrase and Τορο IV, and pharmaceutical compositions thereof. These compounds are useful as inhibitors of bacterial gyrase and Τορο IV activity. The invention also relates to methods of treating bacterial infections in mammals and methods for reducing the amount of bacteria in biological samples. [Prior Art] Bacteria that have long recognized antibiotics, and today they are considered to be a serious worldwide health problem. As a result of drug resistance, some bacterial infections are difficult or even impossible to treat with antibiotics. This problem is particularly acute due to the recent development of multidrug resistance in certain fine strains such as streptococcus pneumoniae (SP), Mycobacterium tuberculosis and Enterococcus. The emergence of vancomycin-resistant enterococci is particularly causing panic because vancomycin is the only effective antibiotic used to treat this infection, and has been considered the "last resort" of many infections. Many other drug-resistant bacteria do not cause life-threatening diseases, such as enterococci, and genes that are resistant to drug resistance are passed on to more deadly organisms such as Staphylococcus aureus, which are common to Methicillin. De Clerq, et al., Current Opinion in Anti-infective Investigational Drugs, 1999, 1, 1; Levy, "The Challenge of Antibiotic Resistance", Scientific American, March 1998). Another concern is how quickly antibiotics are circulating. For example, until the 1960s SP was sensitive to penicillin worldwide, and in 1987 only

O:\90\90896.DOC 1334416 0.02%之SP株在美國具抗藥性。然而，到1995報告抗青黴素 的SP為約百分之七且在美國某些部分高至30%(路易士， FDA消費者雜誌（1995年九月）；Gershman in The Medical Reporter，1997) 0 醫院特別是起抗藥性生物的形成和傳播的中心之作用。 發生在醫院中的感染，已知為醫院感染，目前正變成愈來 愈嚴重的問題。每年有二百萬位美國人在醫院中感染，一 半以上的這些感染抵抗至少一種抗生素。疾病控制中心報 告在1992，超過13,000位的醫院病人死於抗生素治療之細 菌感染（路易 士，”The Rise of Antibiotic-Resistant Infections"， FDA消費者雜諸（FDA Consumer magazine)，1995 年九月）。 由於需要與抗藥性細菌和增加之可用藥物失敗戰鬥，對 於發現新穎抗生素已再生興趣。一種發展新抗生素的引人 策略為抑制DNA促旋酶，一種DNA複製所需且因此為細菌 細胞生長和分化所需之細菌酵素。促旋酶活性也與DNA轉 錄、改質和重組之事件有關。 促旋酶為拓樸異構酶（topoisomerase)之一，催化DNA之拓 樸異構物的互換之酵素的一族（通常參見，Kornberg及Baker, DNA複製（DNA Replication)，第 2版，第 12章，1992，W. Η· Freeman及Co·; Drlica，分子微生物學（Molecular Microbiology)， 1992，6，425; Drlica及Zhao，微生物學和分子生物綜覽 (Microbiology and Molecular Biology Reviews)，1997，61，377)。 促旋酶本身控制DNA超捲曲（supercoiling)及減輕當親代雙股 duplex之DNA股在複製過程期間被未捲繞時所發生之拓樸O:\90\90896.DOC 1334416 0.02% of SP strains are resistant in the United States. However, by 1995 it was reported that anti-penicillin SP was about 7 percent and in some parts of the United States it was as high as 30% (Louis, FDA Consumer Journal (September 1995); Gershman in The Medical Reporter, 1997) 0 Hospital In particular, it plays a role as the center of the formation and spread of drug-resistant organisms. Infections that occur in hospitals, known as nosocomial infections, are becoming more and more serious problems. Two million Americans are infected in hospitals each year, and more than half of these infections are resistant to at least one antibiotic. The Centers for Disease Control reported that in 1992, more than 13,000 hospital patients died of antibiotic-treated bacterial infections (Louis, "The Rise of Antibiotic-Resistant Infections", FDA Consumer Magazine, September 1995) Due to the need to fight against drug-resistant bacteria and increased availability of available drugs, there has been renewed interest in the discovery of novel antibiotics. One approach to the development of new antibiotics is to inhibit DNA gyrase, a DNA replication required and therefore bacterial cell growth and The bacterial enzyme required for differentiation. The gyrase activity is also involved in the events of DNA transcription, modification and recombination. The gyrase is one of the topoisomerases, which catalyze the exchange of the topoisomers of DNA. A family of enzymes (see, generally, Kornberg and Baker, DNA Replication, 2nd ed., Chapter 12, 1992, W. Free Freeman and Co.; Drlica, Molecular Microbiology, 1992, 6 , 425; Drlica and Zhao, Microbiology and Molecular Biology Reviews, 1997, 61, 377). Curling itself controls DNA supercoiling (supercoiling), and reduce the occurrence of the topology of the DNA duplex of shares when the parent is not bifilar wound during the copying process

O:\90\90896.DOC 1334416 應力。促旋酶也催化鬆弛之封閉環狀雙股DNA轉化至比較 有利於重組的負超螺旋（suPerhelical)形式。超捲曲反應機 制包括促旋酶包圍在DNA的一個區域之捲撓’在該區之雙 股斷裂，經由斷裂通過DNA的第二個區域’和再加入該等 斷裂股。該類裂解機制為型II拓樸異構酶（toPoisomerase)的 特性。超捲曲反應藉由ATP至促旋酶的結合驅動。ATP然後 在反應期間水解。此ATP結合和後來水解引起DNA-結合促 旋酶之構形改變，其對其活性是必需的。也已發現DNA超 捲曲（或鬆弛）的程度視ATP/ADP比而定。在ATP不存在下， 促旋酶只能夠鬆弛超捲曲之DNA。 細菌DNA促旋酶為一種由二個A(GyrA)和二個B亞單元 (GyrB)所組成之400千道耳吞（kilodalton)蛋白質四聚物。 DNA的結合和裂解與GyrA有關，然而ATP被GyrB蛋白質結 合和水解。GyrB由具有ATP酶活性的氨基端之區域，和與 GyrA和DNA互相作用的羧基端的區域所組成。對照上，真 核狀態的型II拓樸異構酶為可鬆弛負和正超螺旋，但不能夠 引入負超螺旋的均二聚物。理想地，根據細菌DNA促旋酶 的抑制作用之抗生素將對此酵素具選擇性且對真核狀態的 型II拓樸異構酶較不具活性。 廣泛使用之蒽醌類抗生素抑制細菌DNA促旋酶。蒽醌類 的例子包括早期化合物例如莕咬酸和奥素利酸（oxolinic acid)，以及後期更有效的氟E醌類例如諾氟沙星 (norfloxacin)，環丙沙星（ciprofloxacin)，和秋瓦沙星 (trovafloxacin)。這些化合物結合至GyrA且安定裂解之錯合O:\90\90896.DOC 1334416 Stress. The gyrase also catalyzes the relaxation of the closed circular double-stranded DNA to a more negative super-helix (suPerhelical) form that facilitates recombination. The super-crimp reaction mechanism involves the gyrase enveloping in a region of the DNA, 'double strand breaks in the region, passing through the second region of the DNA', and re-adding the strands. This type of cleavage mechanism is characteristic of the type II topoisomerase. The hyper-crimp reaction is driven by the binding of ATP to gyrase. ATP is then hydrolyzed during the reaction. This ATP binding and subsequent hydrolysis causes a conformational change in the DNA-binding gyrase which is essential for its activity. It has also been found that the degree of DNA super-crimping (or relaxation) depends on the ATP/ADP ratio. In the absence of ATP, gyrase is only able to relax hyper-curled DNA. The bacterial DNA gyrase is a 400 thousand kilodalton protein tetramer composed of two A (GyrA) and two B subunits (GyrB). DNA binding and cleavage are associated with GyrA, whereas ATP is bound and hydrolyzed by the GyrB protein. GyrB consists of a region of the amino terminus having ATPase activity, and a region of the carboxy terminus that interacts with GyrA and DNA. In contrast, the type II topoisomerase of the eukaryotic state is a relaxed negative and positive supercoil, but is not capable of introducing a negative supercoil homodimer. Ideally, an antibiotic that is inhibited by bacterial DNA gyrase will be selective for this enzyme and less active against the eukaryotic type II topoisomerase. The widely used terpenoid antibiotic inhibits bacterial DNA gyrase. Examples of terpenoids include early compounds such as biting acid and oxolinic acid, and later more effective fluorine E quinones such as norfloxacin, ciprofloxacin, and autumn Travafloxacin. These compounds bind to GyrA and are stable to cleavage

O:\90\90896.DOC 1334416 物，因此抑制全部促旋酶功能，導致細胞死亡。然而，抗 藥性也已認知為為此類化合物的問題（WHO報告，”蒽醌類 在食用動物中之使用和對人類健康的衝擊（Use of Quinolones in Food Animals and Potential Impact on Human Health)”，1998)。使用蒽醌類，當使用其他種類之抗生素， 暴露於前化合物的細菌時常很快地發展到對相同種類的更 有效化合物的交叉抗藥性。 有少數結合到GyrB的已知抑制劑。例子包括香豆素、新生黴 素和可默黴素（coumermycin)Al、環p塞立定（cyclothialidine)、辛 諾立定（cinodine)和捨辛定（clerocidin)。香豆素已顯示非常緊 地結合到GyrB。例如，新生黴素製造與蛋白質之氫鍵的網 和幾種疏水性接觸。而新生黴素和ATP確實出現在ATP結合 位置内的結合，在二個化合物的結合取向中有最小的重 疊。重疊分部分為新生黴素的糖單元和ATP腺嘌呤（Maxwell， 微生物學的趨勢（Trends in Microbiology)，1997，5，102)。 對於抗香豆素的細菌，最普遍的點突變是在結合至香豆 素環之羰基的表面精胺酸殘基（大腸桿菌GyrB中的 Argl36)。而具有此突變之酵素顯示較低超捲曲和ATP酶活 性，他們也對被香豆素藥物之抑制作用較不敏感（Maxwell, 分子生物（Mol. Microbiol.)，1993，9，681)。 雖然為促旋酶超捲曲之有效抑制劑，但該等香豆素不被 廣泛地作為抗生素使用。他們通常是不適合的，由於他們 在細菌中的低滲透性、真核狀態毒性和不良水溶解度 (Maxwell，微生物學的趨勢（Trends in Microbiology)， O:\9O\90896.DOC -10- 1334416 1997, 5，102)。想要有一種克服這些缺點的新穎有效的GyrB 抑制劑。該等抑制劑將會是吸引人之抗生素候用物，沒有 煩擾其他類別抗生素之抗藥性問題的歷史。 Μ 延著環DN Α之複製叉運動可在複製錯合物前面和已複製 區域之後兩者產生拓樸變化（Champoux，J. J.，Annu. Rev. Biochem·，2001，70, 3 69-413)。而DNA促旋酶可誘發負超螺 旋以償還在複製叉前面的拓樸應力，一些過捲繞會擴散回 到在precatenanes中所產生之DNA的複製區域。如果不移 除，precatenanes的存在於複製的結束時會造成連結（連鎖） 之子分子。TopolV反應複製期間所形成的分開連鎖之子質 體以及precatenanes的移動，最後允許子分子分離成 (segragation)成子細胞。TopoIV係由二個ParC和2個parE亞 單元以C2E2四聚物所組成（其中c和E單體分別和促旋酶a 和的B單體同源），其需要ATP水解（在e亞單元的N_終端）以 重新起動酵素再進入催化循環。Topo IV在細菌中被高保存 且為細囷複製所必需的（Drlica和Zhao，Microbiol. Mol. Biol. Rev.，1997, 61，377)。 而一些注意已付序於對準Topo IV之parE的抑制劑，已廣 泛地研究較新蒽醌類對ParC區域的作用（Hooper，D. C., Clin. Infect. Dis.，2000, 31 (Suppl 2): S24-28)。已證明莫西 沙星（moxifloxacin)和加替沙星（gatifloxacin)具有抗促旋酶 和Topo IV之更平衡的活性，造成擴大的葛蘭氏陽性和葛蘭 氏陰性細菌範圍以及較低程度之因第一目標突變的抗藥 性。在該等情況中，靈敏度被第二目標對抗菌劑的敏感性 O:\90\90896.DOC • 11 - 1334416 限制。因此，可被多重基本目標有效地抑制之藥劑可 擴大範圍之效力、改良的抗菌效力、改良 的抗卓一目標穿 變的效力，及/或降低抗藥性之自發率。 ’'犬 當抗生素的細菌已變為重要公眾健康問題時，持續 發展更新和更有效的抗生素。更特而兮 ^ ^ 要一種抗生 素，，、表不-種不是先前用於治療細菌感染的新種類化人 物。該等化合物特別可用於治療在抗藥性細菌之形成和; 播變為成愈來愈普遍的醫院中之醫院感染。 【發明内容】 現已發現本發明的化合4勿，和其醫藥上可接受的組合物 作為促旋酶及TopolV的抑制劑是有效的。該等化合物具有 通式I :O:\90\90896.DOC 1334416, thus inhibiting all gyrase function, leading to cell death. However, drug resistance has also been recognized as a problem for such compounds (WHO report, "Use of Quinolones in Food Animals and Potential Impact on Human Health", 1998). With steroids, when other types of antibiotics are used, bacteria exposed to the former compound often develop rapidly to cross-resistance to the same class of more potent compounds. There are a few known inhibitors that bind to GyrB. Examples include coumarin, neomycin and coumermycin Al, cyclothialidine, cinodine and clerocidin. Coumarin has been shown to bind very tightly to GyrB. For example, novobiocin produces a network of hydrogen bonds with proteins and several hydrophobic contacts. While novobiocin and ATP do appear to bind within the ATP binding site, there is minimal overlap in the binding orientation of the two compounds. The overlapping fractions are the saccharide units of novobiocin and ATP adenine (Maxwell, Trends in Microbiology, 1997, 5, 102). For bacteria resistant to coumarin, the most common point mutation is the surface arginine residue (Argl36 in E. coli GyrB) bound to the carbonyl group of the coumarin ring. Enzymes with this mutation show lower super-crimp and ATPase activity, and they are also less sensitive to inhibition by coumarin drugs (Maxwell, Mol. Microbiol., 1993, 9, 681). Although effective inhibitors of gyrase hyperfraction, these coumarins are not widely used as antibiotics. They are usually not suitable due to their low permeability in bacteria, eukaryotic toxicity and poor water solubility (Maxwell, Trends in Microbiology, O:\9O\90896.DOC -10- 1334416 1997 , 5,102). There is a desire for a novel and effective GyrB inhibitor that overcomes these disadvantages. These inhibitors will be attractive antibiotics and have no history of annoying the resistance of other classes of antibiotics.复制 The replication fork motion of the ring DN 可 can produce a topological change both before the replicated complex and after the replicated region (Champoux, J. J., Annu. Rev. Biochem·, 2001, 70, 3 69-413). The DNA gyrase can induce a negative superspin to compensate for the topological stress in front of the replication fork, and some over-winding will diffuse back to the replication region of the DNA produced in the precatenanes. If not removed, the presence of precatenanes will result in a link (chain) of sub-molecules at the end of the copy. The separation of the protonated protons formed during the replication of the TopolV reaction and the movement of the precatenanes ultimately allows the daughter molecules to be separated into daughter cells. TopoIV consists of two ParCs and two parE subunits consisting of C2E2 tetramers (wherein c and E monomers are homologous to gyrase a and B monomers, respectively), which require ATP hydrolysis (in the e subunit) N_terminal) to restart the enzyme and then enter the catalytic cycle. Topo IV is highly preserved in bacteria and is required for fine replication (Drlica and Zhao, Microbiol. Mol. Biol. Rev., 1997, 61, 377). While some attention has been paid to the inhibitors of parE aligned with Topo IV, the role of newer terpenoids in the ParC region has been extensively studied (Hooper, DC, Clin. Infect. Dis., 2000, 31 (Suppl 2)). : S24-28). Moxifloxacin and gatifloxacin have been shown to have a more balanced activity against gyrase and Topo IV, resulting in an expanded range of Gram-positive and Gram-negative bacteria and a lower degree of cause Resistance to the first target mutation. In such cases, the sensitivity is limited by the sensitivity of the second target to the antimicrobial agent O:\90\90896.DOC • 11 - 1334416. Thus, agents that can be effectively inhibited by multiple primary targets can extend the range of potency, improved antimicrobial efficacy, improved efficacy against target penetration, and/or reduce the spontaneous rate of drug resistance. ''Dogs When antibiotic bacteria have become an important public health issue, there is an ongoing development of newer and more effective antibiotics. More special 兮 ^ ^ An antibiotic, a type, is not a new species that was previously used to treat bacterial infections. These compounds are particularly useful for the treatment of hospital infections in the formation of drug-resistant bacteria; and in hospitals that are becoming more and more common. SUMMARY OF THE INVENTION It has now been found that the compound of the present invention and its pharmaceutically acceptable composition are effective as inhibitors of gyrase and TopolV. These compounds have the general formula I:

或其醫藥上可接受的鹽，其中111、112、貿、又、2和環八如 下述所定義。 這些化合物，和其醫藥上可接受的組合物，可使用於治 療或減少細菌感染的嚴重性。特而言之，本發明的化合物 可使用於治療或減少尿道感染、肺炎、前列腺炎、皮膚或 軟組織感染、腹内感染、jk流感染或熱性嗜中性白血球減 少（neutropenic)病人的感染之嚴重性。 O:\90\90896.DOC -12- ^334416 【實施方式】 本發明係有關一種式〗之化合物：Or a pharmaceutically acceptable salt thereof, wherein 111, 112, trade, again, 2 and ring 8 are as defined below. These compounds, and their pharmaceutically acceptable compositions, can be used to treat or reduce the severity of bacterial infections. In particular, the compounds of the invention may be used to treat or reduce the severity of infections in urinary tract infections, pneumonia, prostatitis, skin or soft tissue infections, intra-abdominal infections, jk flow infections or neutropenic patients. Sex. O:\90\90896.DOC -12-^334416 [Embodiment] The present invention relates to a compound of the formula:

R2 或其醫藥上可接受的鹽，其中： 评選自氮、CH或CF ; X選自CH或CF ; Z為0或NH ; R1為苯基或具有1-3個獨立選自氧、氮或硫之雜原子的5-6 貝雜方基環，其中： R1 被 0-3個獨立選自-(T)y-Ar、R，、酮基、C02R，、 OR1、N(R|)2、SR·、no2、鹵素、CN、c(o)n(r，)2、 NR'C(0)R’、S〇2R，、S〇2N(Ri)2或NR，S〇2R，之基取代； y為o或l ; τ為直鏈或支鏈Ci·4亞炫基鏈，其中一個τ之亞甲基單位 可視需要選擇性被-〇-、-ΝΗ-或-S-置換； R'各自獨立選自氫、Cw脂族或5-6員飽和、不飽和，或 具有0-3個獨立選自氮、氧或硫之雜原子的芳基環，其中： R'被0-3個獨立選自卣素、酿I基、r〇、n(r0)2、〇R〇、 C〇2R°、NR〇C(0)R。、C(0)N(R°)2、S〇2R。、s〇2N(R〇)2或 NR°S02R°2基取代，其中： 〇;\90\90896.DOC •13- 1334416 R各自獨立選自氮、Ci_4脂族或5-6貝飽和、不飽和， 或具有0-3個獨立選自氮、氧或硫之雜原子的芳基環， 和其中： 二個在R1的相鄰位置上之取代基可一起形成5_7 員飽和、部份不飽和，或具有〇_3個獨立選自氮、氧 或硫之雜原子的芳基環；R2 or a pharmaceutically acceptable salt thereof, wherein: the evaluation is selected from nitrogen, CH or CF; X is selected from CH or CF; Z is 0 or NH; R1 is phenyl or has 1-3 independently selected from oxygen, nitrogen Or a 5-6 beta heterocyclyl ring of a hetero atom of sulfur, wherein: R1 is independently selected from 0-3 -(T)y-Ar, R, keto, C02R, OR1, N(R|) 2. SR·, no2, halogen, CN, c(o)n(r,)2, NR'C(0)R', S〇2R, S〇2N(Ri)2 or NR, S〇2R, Substituted; y is o or l; τ is a linear or branched Ci·4 sub-strand chain, wherein a methylene unit of τ can be selectively replaced by -〇-, -ΝΗ- or -S- R' is each independently selected from the group consisting of hydrogen, Cw aliphatic or 5-6 member saturated, unsaturated, or an aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein: R' is 0 - 3 independently selected from the group consisting of alizarin, brewing I group, r〇, n(r0)2, 〇R〇, C〇2R°, NR〇C(0)R. , C(0)N(R°)2, S〇2R. , s〇2N(R〇)2 or NR°S02R°2 group substitution, wherein: 〇;\90\90896.DOC •13- 1334416 R are each independently selected from nitrogen, Ci_4 aliphatic or 5-6 Å saturated, not Saturated, or an aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein: two substituents at adjacent positions of R1 may together form a 5-7-saturated, partially unsaturated Or an aryl ring having 〇_3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ar為3-8員飽和、不飽和，或芳基環，具有1-3個獨立選 自氮氧或硫之雜原子的3-7員雜環，或具有i_3個獨立選自 氮、氧或硫之雜原子的5-6員雜芳基環，其中：Ar is a 3-8 membered saturated, unsaturated, or aryl ring having 3 to 3 membered heterocyclic rings independently selected from nitrogen or sulfur heteroatoms, or having i_3 independently selected from nitrogen, oxygen, or a 5-6 membered heteroaryl ring of a hetero atom of sulfur, wherein:

Ar被 0-3個獨立選自 R，、酮基、c〇2R,、〇R,、n(r,)2、 SR，、N02、_ 素、CN、c(〇)N(R，)2、NR,c(〇)R,、s〇2RI、 c(o)r'、S02N(R’)2或nr'so2r，之基取代； R2選自氫或（^_3脂族基；和 環A為一種具有丨-4個獨立選自氮、氧或硫之雜原子的5_6 員雜芳基環’其限制條件為該環在鄰近連接環B的點之位置 具有氫鍵受體，其中： 環A被0-3個獨立選自R，、酮基、c〇2R，、〇R，、N(Rt)2、 SR’、N〇2、齒素、CN、c(〇)N(Ri)2、nr，c(〇)r,、s〇j·、 S〇2N(R')2或NR’S02R’之基取代，和其中： 二個在環A的相鄰位置上之取代基可一起形成5_7員 飽和、部份不飽和，或具朴3個獨立選自氮、氧或硫 之雜原子的芳基環。 如使用在本文t ’除非另有指示否則將應用下列定義。 片5吾視需要選擇性被取抑 " 饭取代之可與片語，，被取代或未被Ar is 0-3 independently selected from R, keto, c〇2R, 〇R, n(r,)2, SR, N02, _, CN, c(〇)N(R,) 2. Substituting NR, c(〇)R, s〇2RI, c(o)r', S02N(R')2 or nr'so2r, R2 is selected from hydrogen or (^_3 aliphatic group; Ring A is a 5-6 membered heteroaryl ring having 丨-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, with the proviso that the ring has a hydrogen bond acceptor at a position adjacent to the point of attachment ring B, wherein : Ring A is 0-3 independently selected from R, keto, c〇2R, 〇R, N(Rt)2, SR', N〇2, dentate, CN, c(〇)N ( Ri), nr, c(〇)r, s〇j·, S〇2N(R')2 or NR'S02R' base substitution, and wherein: two substitutions at adjacent positions of ring A The groups may together form a 5-7 member saturated, partially unsaturated, or aryl ring having 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, unless otherwise indicated, the following definitions will apply. Slice 5, I need to be selectively deprecated " Meal replaced with a phrase, replaced or not

O:\90\90896.DOC •14- 1334416 取代之’’交換使用。除非另有指示否則視需要選擇性被取代 基可在基之每個可取代之位置具有取代基且各取代彼 術語"脂族"或，，脂族基”，如使用在本文令，表示直鏈或支 鏈心-匸8烴鏈，其為完全飽和或包含一或多個不飽和單元， 或單環C3_CS烴或完全飽和或包含一或多個飽和單元但不是 方族之二環(VC〗2烴（在本文中也稱為"碳環"或"環.烷基”），其 具有連接到分子的其餘部分之單—點，其中在該二環環= 之各個環具有3_7個成員。例如，適當脂族基包括（但不限制 於）直鏈或支鏈縣、烯纟、块基和其混雜基例如（環烷基） 烷基、（環烯基）烷基或（環烷基）烯基。 …術語，，院基，，、，’烧氧基”、”經烷基”、”烧氧烷基"和"燒氧 叛基”，單獨使用或作為較大部分的部份包括一到十二個碳 原子之直鏈或支鏈鏈。術語”稀基"和"炔基"單獨使用或或作 為車义大部|的部f分包括二到+二個碳原子之直鍵或支鏈 鍵。 術雜原子表示氮、氧或硫且包括任何氮和硫的氧化 形式’和任何驗性氮四級化形式。術語”氮"也包括雜環環 的個可取代之氮。作為例子，在具有0-3個選自氧、硫或 氮雜原子的—飽和^份殘和環巾，氮可為N(如在3,4_ 氫2H-吡咯基）、NH(如在吡咯啶基中）或nr+(如Ν·取代之 吡咯啶基中）。 術語"不飽和”，如使用在本文中，表示部分具有-或多 個不飽和單元’且包括芳基環。O:\90\90896.DOC •14- 1334416 is used instead of the '' exchange. Unless otherwise indicated, optionally substituted substituents may have substituents at each substitutable position of the radical and each substitution of the term "aliphatic" or, aliphatic radical, as used herein, Represents a linear or branched core-匸8 hydrocarbon chain which is fully saturated or contains one or more units of unsaturation, or a monocyclic C3_CS hydrocarbon or a two ring that is fully saturated or contains one or more saturated units but is not a square group (VC) 2 hydrocarbon (also referred to herein as "carbocyclic" or "cycloalkyl") having a single-point attached to the remainder of the molecule, wherein each of the two rings The ring has 3-7 members. For example, suitable aliphatic groups include, but are not limited to, straight or branched chain counts, olefins, block groups, and their hybrid groups such as (cycloalkyl)alkyl, (cycloalkenyl)alkane. Or (cycloalkyl)alkenyl. ...term,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Or as a larger part of a linear or branched chain of one to twelve carbon atoms. The terms "dilute base" and " "Alkynyl" is used alone or as part of the majority of the car to include a direct bond or a branched bond of two to two carbon atoms. The hetero atom represents nitrogen, oxygen or sulfur and includes any nitrogen and sulfur. Oxidized form 'and any quaternary form of nitrogen. The term "nitrogen" also includes a substitutable nitrogen of a heterocyclic ring. As an example, in the case of having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen - Saturated residue and ring towel, nitrogen can be N (such as in 3,4_hydrogen 2H-pyrrolyl), NH (as in pyrrolidinyl) or nr+ (such as in the pyridinyl group). "Unsaturated", as used herein, means that the moiety has - or more unsaturated units' and includes an aryl ring.

O:\90\90896.DOC -15· 1334416 桁m方基”單獨使用或 基"，"乍為較大部分的部份知^ ” W 基，烷氣基"，或”芳氧 ^ 1伤如在”芳烷 四個環成員之單产 m 土 ，係指具有總數為五到十 缔由 早;衣、二環和三環環系，盆中至/ 統中之環為芳族和其令八中至少一個在系 任·丨丨矣I丨丨 “、先中各¥包含3到7侗環成i 免 〇D方基可與術扭丨，装萁 衣成員。術 中定展交換使用。術語丨|芳基•丨如在· 中疋義也稱為雜芳基環系。 Μ如在下文 術语”雜環"、”雜谱其"4、" & 雜衣基或雜環的，'如使用在本文中f干且 有五到十四個環成員之非芳族單環、 =中表不具 中至少一戋多個 衣或二％環系，其 4夕個％成貝為雜原子，季 個環成員。 y、，.，中的各核包含3到7 術語"雜芳其丨丨，@彼y=t m 1 芳m二 為較大部分的部份如在，，雜 土 β雜芳烷氧基"中係指具有 成員 负〜数為五到十四個環 珉員之早％、二環和三環環系，1 H名分 ，、中至J —個在系統中之 夭至少一個在系統中之環包j -Μ ^ J ^ .. 岜3 一或多個雜原子， 乂「'统中的各環包含3到7個環成員。術語"雜芳基"可 /、術语"雜芳基環11或術語”雜芳族"交換使用。 2語"氫鍵受體，，，如使用在本文中，表示能夠接受氮鍵 的原子。典型的氫鍵受體為硫、氧或氮原子，尤其是sp2_ 混成的氮，氧或硫崎硫。較佳的氫鍵受體為s，混成的氮。 取代基或變數的組合僅在當該組合產生安定或化學能實 行的化合物時可被允許。安定化合物或化學能實行的化合 物為-種當在4代或以下的溫度、在無澄氣或其他化學反 應條件保持至少—個星期時不會實f上改變的化合物。 热習該項技術者顯而易知地本發明某些化合物可以互變 O:\9O\90896.DOC •16- 1334416 異構物形式存在，所有化合物的該等互變異構物形 發明範圍内。 ” 除非另有指示，否則本文所述之結構也意謂包括該結構 ^斤有立體化學形式；也就是’每個不對稱中心之尺和8植 :槿：Γ本發明化合物的單一立體化學異構物以及鏡像 、 非鏡像異構混合物在本發Μ 。μ 說明，否則本文所述之m — u π除非另有 ^, 、，構描也思明包括不同點僅於存在 -個或多個富含同位素原隹 ^ ^ ^ 化口物。例如，具有氫被著 或碳被富含13c-或14c-之碳置換之本結構的化 表1 =::::二_合物可作為例—具 適當環A部分之例子陳述在下表】中。 N^\ a j5 b H 入NH e N*=\ /“N C 1Λ H d H n-n、 ν-ν 人Ν • Η 1 f n=n g N^=\ h Ν^\ m π k 1 f% Ν飞 々 q XI Λ> r P N^=\ 入0O:\90\90896.DOC -15· 1334416 桁m square base" used alone or base ","乍 is part of the larger part ^"W base, alkane base", or "aryl oxygen ^ 1 injury as in the "half of the four ring members of the argon, the total number of five to ten contracted early; clothing, bicyclic and tricyclic ring system, the basin to / in the ring of the ring is Fang At least one of the family and its order is in the department, 丨丨矣I丨丨", the first in each ¥ contains 3 to 7 侗 ring into the 〇 〇 方 方 方 方 方 方 方 方 方 方 方 方 方 方 术 方 方 术 术 术 术 术 术 术 丨 丨 丨 丨It is used interchangeably. The term 丨|aryl; 丨 as in 疋 疋 is also called heteroaryl ring system. For example, the following terms "heterocyclic", "hybrid" "4, "& A clothing group or a heterocyclic ring, 'if used herein, a non-aromatic monocyclic ring having a dry weight of five to fourteen ring members, = at least one of a plurality of clothes or a two-part ring system in the middle table, 4 In the evening, the % of the shells are heteroatoms, and the members of the ring are quarters. The cores of y,,., contain 3 to 7 terms "heterofang, @彼耶=tm 1 芳m二 is the larger part Part of it, in the heterogeneous β heteroarolkoxy group Refers to the early %, bicyclic and tricyclic ring systems with members minus ~ five to fourteen ring members, 1 H points, and medium to J - at least one ring in the system Package j -Μ ^ J ^ .. 岜3 One or more heteroatoms, 乂 "The rings in the system contain 3 to 7 ring members. The term "heteroaryl" can /, term " The aryl ring 11 or the term "heteroaromatic" is used interchangeably. The 2 word "hydrogen bond acceptor, as used herein, denotes an atom capable of accepting a nitrogen bond. Typical hydrogen bond acceptors are sulfur, oxygen or nitrogen atoms, especially sp2_ mixed nitrogen, oxygen or sulphur. A preferred hydrogen bond acceptor is s, a mixed nitrogen. Combinations of substituents or variables are only permissible when the combination produces a stable or chemically active compound. A compound that is stable or chemically active is a compound that does not change at a temperature of 4 or less, at a temperature of 4 or less, and for at least a week without gas or other chemical reaction conditions. It will be apparent to those skilled in the art that certain compounds of the invention may exist in the form of an O:\9O\90896.DOC•16-1334416 isomer form, and such tautomers of all compounds are within the scope of the invention. . Unless otherwise indicated, the structures described herein are also meant to include that the structure has a stereochemical form; that is, 'each asymmetrical center's ruler and 8 plants: 槿: 单一 a single stereochemical difference of the compound of the present invention. Structures as well as mirrored, non-mirromeric heterogeneous mixtures in the present invention. μ Description, otherwise m-u π described herein unless otherwise ^, ,, and the description also includes different points only exist - one or more It is rich in isotope protons. For example, a chemical having a structure in which hydrogen is replaced or carbon is replaced by a 13c- or 14c-rich carbon. Table 1 =::::Di-complex can be used as an example - Examples with appropriate ring A are stated in the following table. N^\ a j5 b H into NH e N*=\ /"NC 1Λ H d H nn, ν-ν Ν Η 1 fn=ng N^ =\ h Ν^\ m π k 1 f% Ν飞々q XI Λ> r PN^=\ into 0

SS

O:\90\90896.DOC •17- 1334416O:\90\90896.DOC •17- 1334416

入。人力In. Human

Ζ Χ?ΝΖ Χ?Ν

dd 〇飞 入卜Dd 〇飞

Sg hh 其中各mA如上述所定義可視需要選擇性被取代。 根據-具體實施例.，式！之環A為一種具有Μ個獨立選自 氮、氧或硫之雜原子的5_員雜婪 ^ 丁丁 π〕貝雜方基ί衣，其限制條件為該環 在鄰近連接環Β的點之位置且有鍅為辨甘山 、 〜j I八百虱鍵叉體，其中該環A如本 文上述所定義地視需要選擇性被取代。 /艮據另一具體實施例，式1之環A為-種具有“3個氮之6· 貝雜方基¥ ’其限制條件為該環在鄰近連接環b的點之位置 具有氮原子，其中該環A如本文上述所定義地視需要選擇性 被取代。 在某些具體實施例中，式Ϊ之環A部分係選自環a、b、c、 d、e、f、g、h、i、j'k、hm、p'q、r's、t、vwx、 y' z' aa' bb、cc、化和“，其中各環A如上述所定義地視 需要選擇性被取代β 在其他具體實施例中，式][之環八部分為係選自環a、f、j、 s、w、丫和z ’其中各環A如上述所定義地視需要選擇性被取Sg hh wherein each mA is selectively substituted as defined above. According to the specific embodiment. Ring A is a 5 员 丁 丁 丁 π π 杂 独立 独立 独立 独立 独立 独立 独立 独立 , , , , , , , , , , , , , , , , , , , , , , , , , , , , The position and the enthalpy are the licy, and the arsenic, wherein the ring A is optionally substituted as desired herein above. According to another specific embodiment, the ring A of the formula 1 is a species having "3 nitrogens of 6 heme squares" and the restriction condition is that the ring has a nitrogen atom at a position adjacent to the point of the connecting ring b, Wherein ring A is optionally substituted as desired herein above. In certain embodiments, ring A of the formula is selected from the group consisting of rings a, b, c, d, e, f, g, h. , i, j'k, hm, p'q, r's, t, vwx, y' z' aa' bb, cc, chemistry and ", wherein each ring A is selectively substituted as required as defined above In other specific embodiments, the eight parts of the formula are selected from the group consisting of rings a, f, j, s, w, 丫, and z' wherein each ring A is optionally taken as defined above.

O:\90\90896.DOC -18- 1334416 代。 當式I之環A為二環雜芳基環時，較佳二環環a部分包括苯 并嘍唑、苯并咪唑、苯并噚唑和喹啉。 根據一具體貫施例’式I的環A上的取代基，如果存在， 係選自酮基、n(r，)2、c(o)n(r，)2、co2R，、_ 素、n(r，）s〇2Ri、 C(0)R|、OR’、或R|。根據另一具體實施例、式J的環A上的 R'取代基包括甲基、乙基、丙基、哌畊基、哌啶基、或嗎 福啉基，其中該R，基視需要選擇性地被R。、N(R(>)2或〇R。取 代。 根據一具體實施例，式丨的！^基為視需要選擇性被取代之 本基。 根據另一具體實施例，式1的尺1基為一種視需要選擇性被 取代之具有1-3個獨立選自氮、氧或硫的雜原子之5_員雜芳 基環。 根據另具體貫施例，式I的R1基為一種視需要選擇性被 取代之具有1_3個氮的5-員雜芳基環。 本發明另一具體貫施例係有關一種式j之化合物其中r1 為-種視需要選擇性被取代之具有卜2個氮的6•員雜芳基 環。 在某些具體實施例中，式嫩丨基係選自__種視需要選擇 !生被取代之苯基或具有1-2個氮的5·6員雜芳基環。在其他具 胃θΉ'Ι卜式I的Κ1基係選自—種視需要選擇性被取代之 ρ比啶-2-基、吡啶_3_基 啶-4-基、嘧啶_5_基、 吡啶-4-基、吡啶酮、嘧啶_2_基 嘧啶-6-基、咪唑·丨_基、咪唑_2_基O:\90\90896.DOC -18- 1334416 generation. When ring A of formula I is a bicyclic heteroaryl ring, the preferred bicyclic ring a moiety includes benzoxazole, benzimidazole, benzoxazole and quinoline. According to a specific example of the substituent on the ring A of formula I, if present, is selected from the group consisting of a keto group, n(r,) 2, c(o)n(r,) 2, co2R, _ 素, n(r,)s〇2Ri, C(0)R|, OR', or R|. According to another embodiment, the R' substituent on ring A of formula J includes methyl, ethyl, propyl, piperidinyl, piperidinyl, or morpholinyl, wherein the R, the base is selected Sexually by R. And N(R(>)2 or 〇R. Substituted. According to a specific embodiment, the base of the formula is a substrate which is optionally substituted as needed. According to another specific embodiment, the rule 1 of the formula 1 The base is a 5-membered heteroaryl ring having 1-3 independently selected from nitrogen, oxygen or sulfur, optionally substituted. According to another embodiment, the R1 group of formula I is a kind of There is a need for a 5-membered heteroaryl ring having 1 to 3 nitrogens which is optionally substituted. Another specific embodiment of the invention relates to a compound of formula j wherein r1 is a species which is optionally substituted as desired a 6-membered heteroaryl ring of nitrogen. In certain embodiments, the formula is selected from the group of __ as desired; a substituted phenyl group or a 5.6 member having 1-2 nitrogens Heteroaryl ring. In other Κ1 系 Ή Ι 式 式 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基_5_yl, pyridin-4-yl, pyridone, pyrimidine-2-ylpyrimidin-6-yl, imidazolium-yl, imidazolium-2-yl

O:\90\90896.D〇C 1334416 咪唑-4-基或咪唑-5-基之環。根據另一具體實施例，式I的 R1基為p比咬-3-基，p比咬-4-基，n比咬酿|，續咬-5-基，或味嗤 -1-基的視需要選擇性被取代之環。 在某些具體實施例中，在式I的R1基上的取代基，當存在 時，係選自鹵素、酮基、-(T)y-Ar、R'、C02R’、OR'、N(R')2、 SR'、C(0)N(R')2、NR’C(0)R'、s〇2R，、S02N(R，)2、或 NR$〇2R·。根據其他具體實施例，在式I的Ri基上的取代 基’當存在時，係選自酮基、氟、氣、N(CH3)2、NHCH2CH3、 NH-環义丙基、NH2、NHC(0)CH3、C(0)NH環丙基、甲基、 乙基、三級-丁基、異丁基、環丙基、異丙基、CH2苯基、 CH2吡啶-3-基、〇H、OCH3、〇CH2CH3、OCH2苯基、OCH2 峨啶-3-基、CH2威啶基、CH2環丙基、或CH2CH2OCH3。 根據一具體實施例，R1被-(T)y-Ar取代，其中為一種直鏈 或支鏈C!·3亞烧基鏈，其中一個τ之亞甲基單位可視需要選 擇性被-0-、-NH-或-S-置換；根據另一具體實施例，τ為直 鏈或支鏈（^-3亞烷基鏈，其中一個τ之亞曱基單位被·〇_、 -ΝΗ_或-S-置換。本發明另一具體實施例係有關一種式j之化 &物，其中r被_(T)y_ ΑΓ取代及Ar為一種視需要選擇性被取 代之具有1-2獨立選自氧 '氮或硫的雜原子之5·6員飽和環。 根據另一具體實施例，式I的Ar基為一種視需要選擇性地被 取代之具有1-3個獨立選自氮、氧或硫的雜原子之％員雜芳 基環。根據另一具體實施例，式1的Ar基為一種視需要選擇 性地被取代之具有丨_3個氮的6_員雜芳基環。另一具體實施 例係有關-種式比化合物’其中^為視需要選擇性地被取O:\90\90896.D〇C 1334416 Imidazol-4-yl or imidazole-5-yl ring. According to another specific embodiment, the R1 group of formula I is p to a -3-yl group, p is more than a -4- group, n is a bite, a bite is a 5-base, or a miso-1-yl group A ring that is optionally replaced as needed. In certain embodiments, a substituent on the R1 group of formula I, when present, is selected from the group consisting of halogen, keto, -(T)y-Ar, R', C02R', OR', N ( R')2, SR', C(0)N(R')2, NR'C(0)R', s〇2R, S02N(R,)2, or NR$〇2R·. According to other specific embodiments, the substituent 'on the Ri group of formula I, when present, is selected from the group consisting of keto, fluoro, qi, N(CH3)2, NHCH2CH3, NH-cyclopropyl, NH2, NHC ( 0) CH3, C(0)NH cyclopropyl, methyl, ethyl, tert-butyl, isobutyl, cyclopropyl, isopropyl, CH 2 phenyl, CH 2 pyridin-3-yl, 〇H , OCH3, 〇CH2CH3, OCH2 phenyl, OCH2 acridine-3-yl, CH2 rididinyl, CH2 cyclopropyl, or CH2CH2OCH3. According to a particular embodiment, R1 is substituted by -(T)y-Ar, wherein is a linear or branched C!·3 alkylene chain, wherein a methylene unit of τ can optionally be -0- , -NH- or -S-substitution; according to another specific embodiment, τ is a linear or branched (^-3 alkylene chain in which one τ of the τ group of τ is 〇_, -ΝΗ_ or -S-substitution. Another embodiment of the invention relates to a compound of formula j, wherein r is replaced by _(T)y_ ΑΓ and Ar is an optionally substituted 1-2 independently selected According to another embodiment, the Ar group of the formula I is optionally substituted with 1-3 independently selected from nitrogen and oxygen. Or a heteroaryl ring of a hetero atom of sulfur. According to another specific embodiment, the Ar group of formula 1 is a 6-membered heteroaryl ring having 丨_3 nitrogens which is optionally substituted as desired. Another specific embodiment is related to the formula of the compound 'where ^ is selectively taken as needed

O:\90\90896.DOC •20- 1334416 代之苯基。 當式I的R1基被-(TVAr取代時，Ar±的取代基之例子包 括函素、OR，、R，、叫n2R，、喊、和 C(〇)Ri。O:\90\90896.DOC •20- 1334416 Substituted phenyl. When the R1 group of the formula I is substituted by -(TVAr, examples of the substituent of Ar± include a element, OR, R, n2R, shout, and C(〇)Ri.

根據一具體實施例，當在式I之的相鄰位置上的二個取 代基-起形成視f要選擇性被取代之稠合至R1的環時，藉 此所形成之核包括5·6員飽和、部份不飽和，或具有㈡個獨 立地選自1、氧或硫之雜原子的芳基環。根據另一具體實 施例’該桐合至Ri之環係選自具有二個氧之％員飽和環或 具有二個氧之卜員飽和環。在該稠合至R1之環上的取代基 之例子包括鹵素，例如氟。 本發明一具體實施例係有關化合物，其中R2選自曱 基、乙基、異丙基、或環丙基。根據另一具體實施例，R2 為甲基或乙基。根據另一具體實施例，式1的尺2為乙基。 根據一具體實施例，本發明係有關式化合物，其中z 為NH。According to a particular embodiment, when the two substituents at adjacent positions of formula I form a ring fused to R1 which is optionally substituted, the core formed thereby comprises 5. 6 The member is saturated, partially unsaturated, or has (ii) an aryl ring independently selected from heteroatoms of 1, oxygen or sulfur. According to another embodiment, the ring of the ligated to Ri is selected from a saturated ring having two oxygen members or a saturated ring having two oxygen. Examples of the substituent on the ring fused to R1 include a halogen such as fluorine. A particular embodiment of the invention is a related compound wherein R2 is selected from the group consisting of decyl, ethyl, isopropyl, or cyclopropyl. According to another specific embodiment, R2 is methyl or ethyl. According to another specific embodiment, the rule 2 of Formula 1 is an ethyl group. According to a particular embodiment, the invention is a compound of the formula wherein z is NH.

根據另一具體實施例，本發明係有關式I之化合物，其中 Z為〇 〇 本發明的化合物落在PCT/US 01/48855所述化合物的種 類中。然而，申請者已發現環A部分之存在，如上述所定義， 賦予令人驚苛和料想不到地增加之促旋酶抑制，Topol V活 性，和抗微生物效力。 根據一具體實施例，本發明係有關一種式π之化合物： 0:\90\90896.DOC -21 -According to another embodiment, the invention relates to a compound of formula I, wherein Z is 〇 〇 The compound of the invention falls within the class of the compound described in PCT/US 01/48855. However, Applicants have discovered that the presence of the Ring A moiety, as defined above, confers a surprising and unexpected increase in gyrase inhibition, Topol V activity, and antimicrobial efficacy. According to a specific embodiment, the invention relates to a compound of the formula π: 0:\90\90896.DOC -21 -

1334416 或其醫藥上可接受的鹽，其中Z、R2和環A如上述所定義和 所述之咪唑環在4-位置視需要選擇性地被C(0)N(R,)2取代 及/或在2-位置被R1取代。因此’本發明另—具體實施例係 有關一種式ΙΙ-a之化合物：1334416 or a pharmaceutically acceptable salt thereof, wherein Z, R2 and ring A are as defined and described above, and the imidazole ring is optionally substituted by C(0)N(R,)2 at the 4-position and/or Or replaced by R1 at the 2-position. Thus, the present invention is directed to a compound of the formula a-a:

或其醫藥上可接受的鹽，其中Z、R2、R'和環A如上述所定 義。 其他描述ΙΙ-a的R2和環A基之具體實施例為該等上式”斤 述者。 其他描述ΙΙ-a的R1基之具體實施例係選自氫或CN4脂族。 根據一具體實施例，本發明係有關一種式II或ΙΙ-a之化合 物，其中Z為NH。 根據另一具體實施例，本發明係有關一種式II或II_a之化 O:\90\90896.DOC •22· 1334416 合物，其中Z為〇。 根據另一具體實施例’本發明係有關一種式III之化合物： ΗOr a pharmaceutically acceptable salt thereof, wherein Z, R2, R' and ring A are as defined above. Other specific embodiments describing the R2 and ring A groups of ΙΙ-a are those of the above formula. Other specific embodiments describing the R1 group of ΙΙ-a are selected from hydrogen or CN4 aliphatic. By way of example, the invention relates to a compound of formula II or ΙΙ-a, wherein Z is NH. According to another embodiment, the invention relates to a formula II or II_a O:\90\90896.DOC •22· 1334416, wherein Z is hydrazine. According to another embodiment, the invention relates to a compound of formula III: Η

ζ>〇 R2ζ>〇 R2

III 或其醫藥上可接受的鹽，其中z、R2和環A如上述所定義， 和所述之吡啶酮環被0-2個獨立選自-(CH2)y-Ar、鹵素、酮 基、R’、C02R'、〇ri、N(R.)2、SR,、c(〇)N(R,)2、NR,c(〇)R，、 SO2R'、S02N(R’）2或NRlS02R，之基取代。 其他描述式III之R2和環A基的具體實施例為該等上式“斤 述者。 其他描述在式III的吡啶酮環上的取代基之具體實施例為 該專上述式I之R1上的較佳取代基。 根據一具體實施例，.本發明係有關一種式ΠΙ之化合物， 其中Ζ為ΝΗ。 根據另一具體實施例，本發明係有關一種式m之化合 物，其中Ζ為0。 根據另一具體實施例，本發明係有關一種式In_a之化合 物，： O:\90\90896.DOC -23- 1334416Or a pharmaceutically acceptable salt thereof, wherein z, R2 and ring A are as defined above, and wherein the pyridone ring is independently selected from 0-2 -(CH2)y-Ar, halogen, keto group, R', C02R', 〇ri, N(R.)2, SR, c(〇)N(R,)2, NR,c(〇)R,, SO2R', S02N(R')2 or NRlS02R , the base is replaced. Other specific examples describing the R2 and ring A groups of formula III are those of the above formula. Other specific examples of substituents described on the pyridone ring of formula III are on R1 of the above formula I. Preferred substituents. According to a particular embodiment, the invention relates to a compound of the formula wherein hydrazine is hydrazine. According to another embodiment, the invention relates to a compound of formula m wherein hydrazine is zero. According to another specific embodiment, the invention relates to a compound of the formula In_a,: O:\90\90896.DOC -23- 1334416

z>〇 R2 III-a 或其醫藥上可接受的鹽’其中z、R，、r2和環a如上述所定 義 其他描述式1114之R2基的具體實施例為該等上式工之R2 基所述者。 其描述在式III-a之環A的他具體實施例為該等上式J之環 A基所述者。 在某些具體實施例中，R，式In_a的吡啶酮環上的取代基 係選自氫或Cm脂族，其中R，視需要選擇性地被苯基或吡啶 基取代。在其他具體實施例中，在式爪心之吡啶酮環上的 取代基R|係選自甲基、乙基、三級_ 丁基、異丁基、環丙基' 異丙基、CH2笨基、CH2吡啶-3-基、CH2哌啶基、CH2環丙 基、或 CH2CH2OHH3。 根據一具體實施例’本發明係有關一種式ni-a之化合 物，其中Z為NH。 根據另一具體實施例，本發明係有關一種式ni_a之化合 物，其中Z為〇。 本發明另一具體實施例有關一種式1¥之化合物： O:\90\90896.DOC •24- 1334416z>R2III-a or a pharmaceutically acceptable salt thereof, wherein z, R, r2 and ring a are as defined above, and other embodiments of the R2 group of formula 1114 are those of the above formula Said. His specific embodiment of ring A, described in Formula III-a, is those described in the ring A of the above formula J. In certain embodiments, R, the substituent on the pyridone ring of formula In_a is selected from hydrogen or a Cm aliphatic group, wherein R, optionally substituted with a phenyl or pyridyl group. In other specific embodiments, the substituent R| on the pyridone ring of the formula is selected from the group consisting of methyl, ethyl, tertiary butyl, isobutyl, cyclopropyl 'isopropyl, CH2 Base, CH2pyridin-3-yl, CH2 piperidinyl, CH2 cyclopropyl, or CH2CH2OHH3. According to a specific embodiment, the invention relates to a compound of the formula ni-a wherein Z is NH. According to another embodiment, the invention relates to a compound of the formula ni_a, wherein Z is deuterium. Another embodiment of the invention relates to a compound of formula 1: O:\90\90896.DOC •24- 1334416

z>〇 R2 或其醫藥上可接受的鹽 述所定義。 IV 其中 y、Z、T ' Ar、 R和環A如上 其他描述式IV的環a*r2基之具體實施例為 工 之環A和R2基所述者。 根據一具體實施例，式IV的Ar基為一種視需要選擇性地 被取代之具有卜2個獨立選自氧、敗或硫之雜原子的5_6員飽 和環。 根據另一具體實施例，式IV的^基為—種視需要選擇性 地被取代之具有1_3個獨立選自氮、氧或硫的雜原子之5•員 雜芳基環。 根據另一具體實施例，式…的心基為一種視需要選擇性 地被取代之具有1-3個氮之6-員雜芳基環。 另一具體實施例係有關一種式IV之化合物，其中Ar為一 種視需要選擇性地被取代之苯基。 根據一具體實施例，本發明係有關一種式IV之化合物， 其中Z為NH。 在式IV的Ar基上之取代基的例子包括鹵素、〇R'、R·、 co2r'、S02R·、酮基、和c(〇)R'。 〇:\9〇y90$96.t)〇C -25- 1334416 R1z>〇 R2 or its pharmaceutically acceptable salt is as defined. IV wherein y, Z, T'Ar, R and ring A are as described above. Specific examples of the ring a*r2 group of formula IV are those described in the ring A and R2 groups. According to a specific embodiment, the Ar group of formula IV is a 5-6 membered saturated ring having two heteroatoms independently selected from oxygen, sulphur or sulfur, optionally substituted as desired. According to another embodiment, the group of formula IV is a 5-membered heteroaryl ring having 1-10 heteroatoms independently selected from nitrogen, oxygen or sulfur, optionally substituted. According to another specific embodiment, the core group of the formula is a 6-membered heteroaryl ring having 1-3 nitrogens which is optionally substituted as desired. Another embodiment is directed to a compound of formula IV wherein Ar is a phenyl group which is optionally substituted as desired. According to a specific embodiment, the invention relates to a compound of formula IV, wherein Z is NH. Examples of the substituent on the Ar group of the formula IV include halogen, 〇R', R., co2r', S02R., ketone group, and c(〇)R'. 〇:\9〇y90$96.t)〇C -25- 1334416 R1

根據另—具體實施例’本發明係有關一種式IV之化合 物，其中Z為0。 本發明另一具體實施例係有關一種式乂之化合物： Μ 或其醫藥上可接受的鹽，其中y、z、R2和上述所定義。 其他t田述式V的R1和R2基之具體實施例該等上㈤式工的Rl 和R2基所述者。 根據一具體實施例，本發明係有關一種式V之化合物，其 中Z為NH。 弋的Ar基上之取代基的例子包括鹵素、〇RI、RI、 C〇2R,' S〇2R,、酮基、和C(〇)R，。 根據另一具赞眘始,, 本發明係有關一種式V之化合物， 其中Z為〇。According to another embodiment, the invention relates to a compound of formula IV wherein Z is zero. Another embodiment of the invention relates to a compound of the formula: hydrazine or a pharmaceutically acceptable salt thereof, wherein y, z, R2 are as defined above. Specific Examples of R1 and R2 Groups of Others V. These are the R1 and R2 groups of the above formula (5). According to a specific embodiment, the invention relates to a compound of formula V, wherein Z is NH. Examples of the substituent on the arylene group include halogen, 〇RI, RI, C〇2R, 'S〇2R, ketone group, and C(〇)R. According to another, the invention relates to a compound of formula V, wherein Z is deuterium.

根據本發明另__ 體實施例係有關一種式乂〗之化合物 (PyArAccording to another aspect of the invention, a compound of the formula (PyAr)

0:\90\90896.DOC -26- 1334416 或其醫藥上可接受的鹽’其中y、Z、T、Ar和R2如上述所定 義。 其他描述式VI的R2基之具體實施例為該等上述式I的r2 基所述者。 根據一具體實施例，式VI的Ar基為一種視需要選擇性被 取代之具有1·2個獨立選自氧、氮或硫的雜原子之5_6員飽和 環。 根據另一具體實施例，式¥1的斛基為一種視需要選擇性 被取代之具有1_3個獨立選自氮、氧或硫之雜原子的5_員雜 芳基環。 根據另一具體實施例，式VI的Ar基為一種視需要選擇性 被取代之具有1-3個氮的6-員雜芳基環。 另一具體實施例係有關一種式VI之化合物，其中Ar為視 需要選擇性被取代之苯基。 根據一具體實施例，本發明係有關一種式VI之化合物， 其中Z為NH。 在式VI的Ar基上之取代基的例子包括鹵素、〇Ri、R，、 C02R’、S02R'、酮基、和C(0)R'。 根據另一具體實施例’本發明係與有關一種式VI之化合 物，其中Z為0。 式I的實例結構陳述於下表2中。 表2. •27·0:\90\90896.DOC -26- 1334416 or a pharmaceutically acceptable salt thereof wherein y, Z, T, Ar and R2 are as defined above. Other specific embodiments of the R2 group describing Formula VI are those described for the r2 group of Formula I above. According to a specific embodiment, the Ar group of formula VI is a 5-6 membered saturated ring having from 1. 2 heteroatoms independently selected from oxygen, nitrogen or sulfur, optionally substituted. According to another embodiment, the fluorenyl group of formula 1 is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, optionally substituted. According to another specific embodiment, the Ar group of formula VI is a 6-membered heteroaryl ring having 1-3 nitrogens which is optionally substituted as desired. Another embodiment is directed to a compound of formula VI wherein Ar is optionally substituted phenyl. According to a specific embodiment, the invention relates to a compound of formula VI, wherein Z is NH. Examples of the substituent on the Ar group of the formula VI include halogen, 〇Ri, R, C02R', S02R', a ketone group, and C(0)R'. According to another embodiment, the invention is directed to a compound of formula VI wherein Z is zero. An example structure of Formula I is set forth in Table 2 below. Table 2. •27·

O:\90\90896.DOC 1334416O:\90\90896.DOC 1334416

O:\90\90896.DOC •28- 1334416O:\90\90896.DOC •28- 1334416

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1-45 1-46 1-481-45 1-46 1-48

n. 7 7 ^-NH N: HN >=° —On. 7 7 ^-NH N: HN >=° —O

1-50 1-471-50 1-47

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1-631-63

1-641-64

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1-75 1-76 1-77 1-78 OH1-75 1-76 1-77 1-78 OH

1-83 1-84 1-85 1-86 O:\9O\90896.DOC •32 13344161-83 1-84 1-85 1-86 O:\9O\90896.DOC •32 1334416

1-87 1-88 1-89 1-901-87 1-88 1-89 1-90

1-91 1-92 1-93 1-941-91 1-92 1-93 1-94

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-ΝΗ 1-135-ΝΗ 1-135

Ο ^-ΝΗ ΝΟ ^-ΝΗ Ν

1-137 1-1381-137 1-138

1-139 1-140 1-141 1-1421-139 1-140 1-141 1-142

Ο 1-143 1-144 1-145 1-146Ο 1-143 1-144 1-145 1-146

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°^°°^°

1-23 1 1-232 1-233 1-2341-23 1 1-232 1-233 1-234

1-235 1-236 1-237 1-2381-235 1-236 1-237 1-238

1-239 1-240 1-241 1-2421-239 1-240 1-241 1-242

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1-295 本發明之化合物一般可藉由熟習該項技術者已知用於類 似化合物的方法，如該等下示一般流程卜π，ΠΙ，和W和 下述實例舉例說明之方法製備。1-295 The compounds of the present invention can generally be prepared by methods known to those skilled in the art for analogous compounds, such as those illustrated in the general schemes π, ΠΙ, and W, and the examples exemplified below.

流程IProcess I

⑻(8)

CN 上述流程I表示一種製備可用於製備本發明化合物的N，_ 烷基-N-氰基脲類（3)之一般方法，其中Z為NH。在步驟 中，胺基氰（2)以在氫氧化鈉水溶液中的異氰酸烷酯處理， 以在酸化之後提供化合物3。熟習該項技術者應了解異氰酸 烷酯之變體可接受流程I之反應條件以形成N，_烷基_ N _氰基 脲類之變體。 O:\90\90396.DOC 46- 1334416CN The above Scheme I represents a general method for preparing N,_alkyl-N-cyanoureas (3) which can be used to prepare the compounds of the present invention, wherein Z is NH. In the step, the amino cyanide (2) is treated with an alkyl isocyanate in an aqueous sodium hydroxide solution to provide the compound 3 after acidification. Those skilled in the art will appreciate that variants of the alkyl isocyanate accept the reaction conditions of Scheme I to form a variant of the N,-alkyl-N-cyanourea. O:\90\90396.DOC 46- 1334416

流程IIProcess II

10 試劑和條件：（a)過硼酸鈉，HOAc ’ 55°C (b)環A，NaH ’ THF ; (c)NH3 » MeOH > EtOH » 80°C ； (d) R1-B(OH)2 > Pd(PPh3)4 > NaHC03，H20，THF，70〇C ; (e)H2，Pd/C，EtOAc ; (f)3， H2S04，95°C ; (g)2-甲基-2-硫假月尿（thiopseudourea)，R2-氯 甲酸醋。 上述流程II顯示製備一種本發明的苯并咪唑化合物之一 般方法，其中Z為NH或Ο。溴基-苯胺（4)以過硼酸鈉和乙酸 處理而形成二氟基-硝基化合物（5卜化合物5在氩化鈉存在 下以環A處理以提供二芳基化合物6。化合物6之其餘氟基以 O:\9O\90896.DOC -47- 1334416 氨置換以形成胺化合物（7八2-硝基-5-溴基苯胺（7)然後於步 驟（d)，在鈀存在下偶合至芳基硼酸，以形成三-芳基化合物 (8)。還原化合物8的硝基以形成二胺基化合物，其以ν'-烷 基-Ν-氰基脲（3)處理以形成式j的苯并咪唑化合物，其中ζ 為 ΝΗ(9)。 或者’中間物8可用以形成式I的化合物，其中ζ為〇。化 合物10係藉由，還原到二胺基化合物之後，根據L z Kruse 等人描述在J. Med. Chem. 1989，32，409-417之方法以2-曱基 -2-硫假脲和r2_氯甲酸酯處理8而形成。熟該項技術者應知 描述在上述流程〗！之反應可接受本發明之R1及環A的變體。 在一替代方法中’中間物8以N，N-二乙基羧基_2-曱基_2_ 硫假脲或N，N_二乙基脲醯胺基-2-甲基-2-硫假脲處理分別 地形成化合物10和9。N，N_二乙基羧基_2_曱基_2_硫假脲和 N，N-二乙基脲醯胺基_2_曱基_2_硫假脲描述在下述實例中。 流程ΠΙ10 Reagents and conditions: (a) sodium perborate, HOAc '55 ° C (b) ring A, NaH 'THF; (c) NH3 » MeOH > EtOH » 80 ° C; (d) R1-B(OH) 2 > Pd(PPh3)4 > NaHC03, H20, THF, 70 〇C; (e) H2, Pd/C, EtOAc; (f) 3, H2S04, 95 ° C; (g) 2-methyl- 2-thiohypourea (thiopseudourea), R2-chloroformic acid vinegar. The above Scheme II shows a general method for preparing a benzimidazole compound of the present invention, wherein Z is NH or hydrazine. Bromo-aniline (4) is treated with sodium perborate and acetic acid to form a difluoro-nitro compound (5 compound 5 is treated with ring A in the presence of sodium hydride to provide the diaryl compound 6. The remainder of compound 6 The fluorine group is substituted with O:\9O\90896.DOC -47-1313416 to form an amine compound (7-octa-2-nitro-5-bromoaniline (7) and then coupled to the step (d) in the presence of palladium to Arylboronic acid to form a tri-aryl compound (8). The nitro group of compound 8 is reduced to form a diamine compound which is treated with ν'-alkyl-indole-cyanourea (3) to form formula j. a benzimidazole compound, wherein ζ is ruthenium (9). Or 'Intermediate 8 can be used to form a compound of formula I, wherein ruthenium is ruthenium. Compound 10 is obtained by reduction to a diamine compound, according to Lz Kruse et al. The method described in J. Med. Chem. 1989, 32, 409-417 is formed by treating 8 with 2-mercapto-2-thioprostyl and r 2 chloroformate. It should be known to those skilled in the art that The reaction of the above procedure can accept the variants of R1 and ring A of the present invention. In an alternative method, 'intermediate 8 is N,N-diethylcarboxyl-2-fluorenyl-2- thiourea or N N-diethylureaamino-2-methyl-2-thioprostol treatment separately forms compounds 10 and 9. N,N-diethylcarboxy_2-indenyl-2-sulfuronamide and N , N-diethylureaamino 2,0-yl-2-dethiourea is described in the following examples.

O:\9O«08%.DOC -48 - 1334416 試劑和條件：（a)pd(dppf)Cl2/KOAc，DMSO，80°C ;和（b) Cu(〇Ac)2Mb 咬，DMF。O:\9O«08%.DOC -48 - 1334416 Reagents and conditions: (a) pd(dppf)Cl2/KOAc, DMSO, 80 °C; and (b) Cu(〇Ac)2Mb bite, DMF.

上述流程III顯示一種使用實質上與該等Kiyomori A.; Marcoux, J.-F.; Buchwald, S. L., Tetradhedron Letters, 40 » (1999)2657-2660所述之方法製備式Π-a化合物的一般方 法。化合物7在Pd(dppf)/乙酸鉀存在下在DMSO中以二硼酸 酯處理以產生中間物11。化合物11在乙銅酸存在下以 4-C(0)N(R’）2·咪唑處理以形成4-C(0)N(R')2-咪唑-1-基化合 物12。式ΙΙ-a的化合物係如流程π，步驟（e)、（f)和（g)所述 從化合物12製備。 雖然4-C(0)N(R')2_咪唑用以舉例，但熟習該項技術者應 了解R1基之變體可接受步驟（c)之置換反應以形成本發明化 合物之變體。通常，硼酸酯中間物丨丨可以Ri_ _化物或r1_ 三氟甲烷磺酸鹽之變體處理，使用熟習該項技術者已知的 方法，形成中間化合物12,，如下所示。使用該等本文所列 或熟習該項技術者已知的方法，化合物12’可用於製備本發 明之化合物9和1〇 ,如上述流程所述。The above Scheme III shows a general preparation of a compound of the formula a-a using a method substantially as described in the methods of Kiyomori A.; Marcoux, J.-F.; Buchwald, SL, Tetradhedron Letters, 40 » (1999) 2657-2660. method. Compound 7 was treated with diborate in DMSO in the presence of Pd(dppf) / potassium acetate to give intermediate 11. Compound 11 was treated with 4-C(0)N(R')2.imidazole in the presence of acetylic acid to form 4-C(0)N(R')2-imidazol-1-yl compound 12. The compound of the formula a-a is prepared from the compound 12 as described in Scheme π, steps (e), (f) and (g). While 4-C(0)N(R')2-imidazole is exemplified, those skilled in the art will appreciate that the variant of the R1 group accepts the displacement reaction of step (c) to form a variant of the compound of the invention. Typically, the boronate intermediate is treated with a variant of Ri_- or r1_trifluoromethanesulfonate, and intermediate compound 12 is formed using methods known to those skilled in the art, as shown below. Compound 12' can be used to prepare compounds 9 and 1 of the present invention, as described in the above scheme, using such methods as are listed herein or known to those skilled in the art.

O:\90\90896.DOC -49· 1334416O:\90\90896.DOC -49· 1334416

流程IVProcess IV

試劑和條件：（a); (b)NH4〇H/二噚烷，回流；（C)pd(pph3)4/THF， 回流；和（d)Na2C03/DMF，加熱。 上述流程IV顯示一種製備式Π-a的化合物之替代方法。化 合物13被硝化而形成μ。化合物μ以氫氧化銨處理而形成 胺基化合物15。化合物15的溴基在THF中於Pd(PPh3)4試劑 存在下以BrZn-環A處理而形成化合物16。化合物16在碳酸 鈉存在下以4-C(0)N(R')2·味嗤處理而形成4_c(〇)n(R，）2-咪 唑-1-基化合物18。式ll-a的化合物然後如流程π，步驟（e)、 ⑴和（g)所述從化合物18製備。 熟習该項技術者應了解本發明化合物之變體可根據流程 I、II、III和IV的一般方法、該技藝中已知的方法和下述合 成實例製備。 本發明的化合物以酵素的化驗測定為促旋酶和τορο IV 之有效抑制劑。這些化合物也已顯示在抗微生物敏感性化Reagents and conditions: (a); (b) NH4〇H/dioxane, reflux; (C) pd(pph3)4/THF, reflux; and (d) Na2C03/DMF, heated. The above Scheme IV shows an alternative method for preparing a compound of the formula Π-a. Compound 13 is nitrated to form μ. The compound μ is treated with ammonium hydroxide to form an amine compound 15. The bromo group of compound 15 is treated with BrZn-ring A in the presence of Pd(PPh3)4 reagent in THF to form compound 16. Compound 16 was treated with 4-C(0)N(R')2·miso in the presence of sodium carbonate to form 4-c(〇)n(R,)2-imazol-1-yl compound 18. The compound of formula ll-a is then prepared from compound 18 as described in Scheme π, steps (e), (1) and (g). Those skilled in the art will appreciate that variations of the compounds of the invention can be prepared according to the general procedures of Schemes I, II, III and IV, methods known in the art, and the following synthetic examples. The compounds of the present invention are assayed as active inhibitors of gyrase and τορο IV by enzyme assays. These compounds have also been shown to be antimicrobially sensitive

O:\90\90896.DOC -50- 1334416 驗中具有抗微生物活性❶在本發明中利用作為促旋酶或 Τορο IV的抑制劑之化合物的活性可在根據該技藝已知的 方法在活體外、活體内或細胞株中化驗。用於酵素和抗微 生物敏感性化驗兩者之條件陳述在下列實例中。 根據另一具體實施例，本發明提供一種組合物，其包含 本發明的化合物或其醫藥上可接受的鹽和醫藥上可接受= 載體、佐劑或媒液。化合物在本發明組合物t的量為致使 在生物樣品或病人中可有效檢測地抑制促旋酶，τ〇ρ〇ιν， 或可測定地減少細g量之量。較佳地調配本發明組合物用 於投予至需該、组合物之病人。最#，調配本發明組合物用 於口服投予到病人。 術語”生物樣品”，如使用在本文中，包括（沒有限制）細胞 培養物或其萃取物；得自哺乳動物之生檢材料或其萃取 物，和血液、唾液、尿、糞、精液、淚或其他體液或其萃 取物。 在生物樣品中的促旋酶及/或τ〇ρ〇 Iv之活性的抑制作用 可使用於熟習該項技術者已知的多種目的。該等目的例子 包括（但不限制於）輸血、器官移植、生物樣品儲存和生物化 驗。 術語"病人”，如使用在本文中，表示一種動物，較佳哺 乳動物’和最佳為人。 術语醫藥上可接受的載體、佐劑或媒液，，係指不破壞與 其調配在一起之化合物的藥理學活性的非毒性載體、佐劑 或媒液。可使用於本發明組合物中之醫藥上可接受的載O:\90\90896.DOC -50- 1334416 The activity of the compound having an antibacterial activity in the present invention using an inhibitor as a gyrase or Τορο IV may be in vitro in a method known to the art. In vivo, or in a cell strain. The conditions for both enzyme and anti-microbial sensitivity assays are set forth in the following examples. According to another specific embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable = carrier, adjuvant or vehicle. The amount of the compound in the composition t of the present invention is such that the gyrase, τ〇ρ〇ιν, or measurably reduces the amount of fine g in a biological sample or patient can be effectively detected. The compositions of the present invention are preferably formulated for administration to a patient in need of such compositions. Most #, the compositions of the invention are formulated for oral administration to a patient. The term "biological sample", as used herein, includes (without limitation) cell culture or an extract thereof; biopsy material derived from a mammal or an extract thereof, and blood, saliva, urine, feces, semen, tears Or other body fluids or their extracts. Inhibition of the activity of gyrase and/or τ〇ρ〇 Iv in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include (but are not limited to) blood transfusions, organ transplants, biological sample storage, and bioassays. The term "patient", as used herein, denotes an animal, preferably a mammal' and preferably a human. The term pharmaceutically acceptable carrier, adjuvant or vehicle, means not disrupting its formulation. Pharmacologically active non-toxic carrier, adjuvant or vehicle for a compound which can be used in the pharmaceutically acceptable carrier of the compositions of the invention

O:\90\90896.DOC -51 - 1334416 體、佐劑或媒液包括（但不限制於）離子交換劑、氧化鋁、硬 脂酸鋁、卵磷脂、血清蛋白質，例如人類血清白蛋白、緩 衝液物質例如魏鹽、甘胺酸、山梨酸、山梨酸鉀、飽和 植物脂肪酸的部分甘油脂混合物、水、鹽或電解質、例如 二精蛋白硫酸鹽、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽、 膠體矽石、三矽酸鎂、聚乙烯吡咯啶酮、纖維素基物質、 聚乙二醇、羧甲基纖維素鈉' 聚丙烯酸酯、 氧丙烯-嵌段共聚物、聚乙二醇和羊毛脂肪。 術語，，可檢測地抑制”，如使用在本文中表示可測量的促 旋酶或τ〇Ρ〇ιν之變化，在包含該組合物和促旋酶或τ〇ρ〇ιν 的樣品和包含促旋酶或TGpQ IV而沒有該組合物的相等樣 品之間的活性。 如使用在本文中，術語"可測量地減少細菌量，，，如使用 在本文中表示在包含該組合物的樣品和只包含細菌的樣品 之間的細菌數的可測量變化。 "醫藥上可接受的鹽”表示本發明化合物的任何非毒性 鹽’其-旦投接受者’能夠直接或間接地提供本發明 的化合物或其抑制活性代謝產物或殘餘物。如使用在本文 中：術語"其抑制活性代謝產物或殘餘物"表示其代謝產物 或殘餘物也為促旋酶及Top〇 IV的抑制劑。 本發明化合物之醫藥上可接受的鹽包括該等得自醫藥上 可接受無機和有機酸和驗之鹽。適當酸鹽之例子包括乙酸O:\90\90896.DOC -51 - 1334416 Body, adjuvant or vehicle including, but not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, Buffer substances such as Wei salt, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes, such as disintrin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorine Sodium, zinc salt, colloidal vermiculite, magnesium tridecanoate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose 'polyacrylate, oxypropylene-block copolymer, Polyethylene glycol and wool fat. The term "detectable inhibition", as used herein, refers to a change in measurable gyrase or τ〇Ρ〇ιν, in a sample comprising the composition and gyrase or τ〇ρ〇ιν and inclusion Cyclonease or TGpQ IV without activity between equal samples of the composition. As used herein, the term "measured to reduce the amount of bacteria, as used herein, is expressed in a sample comprising the composition and A measurable change in the number of bacteria between samples containing only bacteria. "Pharmaceutically acceptable salt" means that any non-toxic salt of the compound of the present invention can be provided directly or indirectly by the present invention. A compound or its inhibitory active metabolite or residue. As used herein: the term "inhibiting active metabolites or residues" means that its metabolites or residues are also inhibitors of gyrase and Top〇 IV. Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and salts. Examples of suitable acid salts include acetic acid

鹽、己"一酸鹽、藻酸趟、夭門久島缺BiS 天門冬虱酸鹽、苯甲酸鹽、笨磺 酸鹽、硫酸風鹽、丁於臨 ΚΛ 11彳宁棣馱鹽、樟腦酸鹽、樟腦磺Salt, hexahydrate, bismuth alginate, bismuth island, BiS aspartate, benzoate, stupid sulfonate, sulfuric acid, salt, Ding in Linyi, 11 彳Nings, camphor Acid salt, camphor

O:\9O\90896.DOC -52- 1334416 酸鹽、環戊烧丙酸鹽、二葡糖酸鹽（digluconate)、十二基硫 酸鹽、乙烷磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽 (glucoheptanoate) ' 甘油鱗酸鹽（glycerophosphate)、甘醇酸 鹽、半硫酸鹽（hemisulfate)、庚酸鹽、己酸鹽、鹽酸鹽、漠 酸鹽、碘酸鹽、2-羥基乙烷磺酸鹽、乳酸鹽、順-丁烯二酸 酯、丙二酸鹽、甲烷磺酸鹽、2-莕磺酸鹽、煙酸鹽、硝酸 鹽、草酸鹽、palmoate、果膠酯酸鹽、過硫酸鹽、3-苯基丙 酸鹽、磷酸鹽、苦味酸鹽、特戊酸酯、丙酸鹽、水楊酸鹽、 琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽和 十一烷酸鹽。其他酸’例如草酸，其本身不為醫藥上可接 受的’可使用於製備在獲得本發明化合物和其醫藥上可接 受的酸加成鹽中作為中間物使用之鹽。 得自適當鹼的鹽包括鹼金屬（例如，鈉和鉀）、鹼土金屬（例 如’鎂）、敍和Ν+((^.4烷基h鹽。本發明也預見本文所揭示 之化合物的任何含鹼性氮之基的四級化作用。水或油_溶性 或分散性產物可藉由該等四級化作用獲得。 本發明的組合物可以口服、非經腸道、吸入喷霧、局部、 直腸、經鼻 '經頰、陰道或經由植入儲存物投予。術語"非 經腸道’’如使用在本文中包括皮下、靜脈内、肌肉内、關節 内、滑液囊内、胸骨内、鞠内、肝内、病灶内和顧内注射 或灌注技術。較佳，該等組合物以口服、腹膜内或靜脈内 投予。本發明組合物之滅菌注射形式可為水或油質懸浮 液。這些懸浮液可根據該㈣已知技術使用衫分散劑或 濕满誠懸浮劑調配。滅菌注射製劑也為在非毒性非經腸O:\9O\90896.DOC -52- 1334416 acid salt, cyclopentane propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, anti-butene Diacid salt, glucoheptanoate 'glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, acid salt, iodine Acid salt, 2-hydroxyethane sulfonate, lactate, maleate, malonate, methanesulfonate, 2-anthracenesulfonate, nicotinate, nitrate, oxalate , palmoate, pectate ester, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartaric acid Salt, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic acid, which are not themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from suitable bases include alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., 'magnesium), and yttrium (+.4 alkylh salts. Any of the compounds disclosed herein are also contemplated by the present invention. Quaternization of basic nitrogen-containing groups. Water or oil-soluble or dispersible products can be obtained by such quaternization. The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topical. , rectal, nasally, buccally, vaginally or via implanted storage. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, synovial sac, Intrasternal, intraorbital, intrahepatic, intralesional and intracoronary injection or perfusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions of the invention may be water or oil. Suspensions. These suspensions can be formulated according to the (4) known technique using a shirt dispersing agent or a wet maneuvering suspension. The sterile injectable preparation is also in a non-toxic parenteral.

O:\90\90896.DOC -53- 1334416 道-可接受的稀釋劑赤，六免丨 次，合知丨中之滅菌注射溶液或懸浮液， :在:’3丁二醇中的溶液。可使用之可接受的媒液和溶劑為 水、Rlnger氏溶液和等張氯化納溶液。除此之外，滅菌之 不揮發性油類習知可作為溶劑或懸浮介質使用。 為此目的，可使用任何混和不揮發性油包括合成單-或二_ 甘油脂。脂肪酸，例如油酸和其甘油脂衍生 射製劑中，如為天自然料上可接/用於主 衆上了接又的油類，例如撖欖油 咖油，尤其是他們的聚氧乙基化變體。這些油溶液或 懸淨液也可包含長鏈醇稀釋劑或分散劑，例如缓甲基纖維 或瓜使用於包括乳液和懸浮液之醫藥上可接受的劑型之 調配中的相似分散劑。為了調配也可使用其他一般使用之 界5· 11劑例如Tween，外㈣和普遍使用在醫藥上可接 受的固體、液體或其他劑型之製備中的其他乳化劑或生物 利用率增強劑。 月醫藥上可接梵的組合物可以包括(但不限制於)膠 囊、錠劑、水懸浮液或溶液之任何口服可接受的劑型而口 予在口服使用之錠劑的情況中，一般所使用之載體 匕括礼糖和玉米澱粉。也典型地加入潤滑劑，例如硬脂酸 鎮。。對於膠囊形式之口服投予，彳用的稀釋劑包括乳糖及 乾燥之玉米澱粉。當水懸浮液需要口服使用時，活性成分 與礼化和懸浮劑合併。如果需要，也可加入某些甜味、矯 味或著色劑。 或者，本發明醫藥上可接受的組合物可以直腸投予之栓 劑的形式投予。這些可藉由混合藥劑與在室溫為固體但在O:\90\90896.DOC -53- 1334416 Channel-acceptable thinner red, six free times, known as sterile injectable solutions or suspensions, in ::3 butanediol solution. Among the acceptable vehicles and solvents that may be employed are water, Rlnger's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any mixed fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glycerolipid-derived preparations, such as oils that can be attached to the natural ingredients, such as eucalyptus oil, especially their polyoxyethyl Variant. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as a slow methyl fiber or a similar dispersing agent used in the formulation of a pharmaceutically acceptable dosage form comprising an emulsion and a suspension. Other emulsifiers or bioavailability enhancers which are commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for the formulation of other general use agents such as Tween, exo (iv) and commonly used. The monthly medicinal composition can include, but is not limited to, any orally acceptable dosage form of a capsule, lozenge, aqueous suspension or solution, and is generally used in the case of a tablet for oral use. The carrier consists of sugar and corn starch. Lubricants such as stearic acid are also typically added. . For oral administration in the form of a capsule, the diluent used includes lactose and dried corn starch. When the aqueous suspension is to be used orally, the active ingredient is combined with the ritual and suspending agents. Some sweetness, flavor or coloring agent can also be added if desired. Alternatively, the pharmaceutically acceptable composition of the present invention can be administered in the form of a rectal administration of a suppository. These can be mixed with the agent and are solid at room temperature but in

O:\90\90896.DOC -54- 直腸度為液體且因此在直腸熔化以釋放藥物之適當非刺 激性賦形劑製備。該等材料包括可可奶油、蜂蝶和聚乙稀 二醇類。 本發明醫藥上可接受的組合物也可局部地投予，尤其當 m療之目標包括藉由局部施用容易接近的區域或器官時， 包括眼睛、皮膚或下腸道之疾病。適當局部調配物容易地 製備用於各該等區域或器官。 下腸遏的局部應用可以直腸栓劑調配物（參見上述）或適 田的灌腸調配物產生。也可使用局部經皮貼片。 對於局部應用，醫藥上可接受的組合物可調配成包含懸 净或溶解在一或多種載體中之活性組份的適當軟膏。用於 本發明化合物局部投予的載體包括（但不限制於）礦物油、液 體礦脂、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、 乳化蝶和水。或者’醫藥上可接受的組合物可調配成包含 懸浮或溶解在一或多種可接受載體中之活性組份的適當乳 液或乳膏。適當載體包括（但不限制於）礦物油，山梨糖醇酐 單硬脂酸酯，聚山梨酯60十六烷基酯蠟、鯨臘基醇、2_辛 基十二醇、苯曱醇和水。 為了眼用，醫藥上可接受的組合物可調配成在等張、pH 調節之滅菌鹽水中之微粒化懸浮液，或，較佳，在等張、 PH調節滅菌鹽水中之溶液，有或沒有防腐劑例如 benZyUlkonium氯化物。或者，為了眼用，醫藥上可接受的 組合物可調配成軟膏例如凡士林。 本發明醫藥上可接受的組合物也可藉由鼻用氣溶膠或吸O:\90\90896.DOC -54- Preparation of a suitable non-irritating excipient with a rectal fluid that is therefore melted in the rectum to release the drug. Such materials include cocoa butter, humming butterflies and polyethylene glycols. The pharmaceutically acceptable compositions of the present invention may also be administered topically, especially when the target of m treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these regions or organs. Topical application of lower intestinal depression can be produced by a rectal suppository formulation (see above) or an adapted enema formulation. Local transdermal patches can also be used. For topical application, a pharmaceutically acceptable composition can be formulated into a suitable ointment comprising the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsified butterfly, and water. Alternatively, the pharmaceutically acceptable composition can be formulated as a suitable emulsion or cream comprising the active component suspended or dissolved in one or more acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60 cetyl ester wax, cetyl alcohol, 2-octyldodecanol, benzofuranol and water . For ophthalmic use, the pharmaceutically acceptable composition can be formulated as a micronized suspension in isotonic, pH adjusted sterile saline or, preferably, in isotonic, pH adjusted sterile saline, with or without Preservatives such as benZyUlkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition can be formulated into an ointment such as petrolatum. The pharmaceutically acceptable compositions of the invention may also be aerosolized or absorbed by the nose

O:\90\90896.DOC -55- 1334416 入投予。該等組合物係根據醫藥調配技藝已知的技術製備 且可製備成在鹽水中之溶液，使用苯甲醇或其他適當防腐 劑、提高生物利用率的吸收促進劑、碳氟化合物及/或其他 習知溶解化劑或分散劑。 最較佳地，本發明醫藥上可接受的組合物被調配為口服 投予。 在每天約0.01和約100毫克/公斤體重之間，較佳每天0.5 和約75毫克/公斤體重之間和最較佳每天約1和50毫克/公斤 體重之間的活性成分化合物的劑量含量可用於由細菌例如 肺炎雙球菌（streptococcus pneumoniae)、釀膿鏈球菌 (streptococcus pyogenes)、糞腸球菌（Enterococcus faecalis)、腸 球菌（Enterococcus faecium)、克雷白氏肺炎桿菌（Klebsiella pneumoniae )、腸細菌屬（Enterobacter sps.)、變形桿菌屬 (Proteus sps·)、綠膿桿菌、大桿腸菌、黏質沙雷氏菌（Serratia marcesens)、金黃色葡萄球菌、Coag. Neg. Staph、流感嗜血 桿菌（Haemophilus influenzae)、炭疽桿菌（Bacillus anthracis)、 肺炎黴聚菌（Mycoplasma pneumoniae)、莫拉斯氏菌屬 (Moraxella catarralis)、肺炎披衣菌（Chlamydia pneumoniae)、嗜 肺性退伍軍人桿菌（Legionella pneumophila)、結核分枝桿菌 (Mycobacterium tuberculosis)、表皮葡萄球菌（Staphylococcus epidermidis)或幽門螺旋桿菌（Helicobacter pylori)所引起之細 菌感染的預防及治療之單一治療。 典型地，本發明之醫藥組合物將投予每天從約1到5次或 或者，以連續灌注。或，可選擇地，本發明的組合物可以O:\90\90896.DOC -55- 1334416 Into the vote. The compositions are prepared according to techniques known in the art of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers that enhance bioavailability, fluorocarbons, and/or other Know the dissolving agent or dispersing agent. Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Dosage levels of active ingredient compounds between about 0.01 and about 100 mg/kg body weight per day, preferably between 0.5 and about 75 mg/kg body weight per day and most preferably between about 1 and 50 mg/kg body weight per day are available From bacteria such as Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter (Enterobacter sps.), Proteus sps., Pseudomonas aeruginosa, S. cerevisiae, Serratia marcesens, Staphylococcus aureus, Coag. Neg. Staph, Haemophilus influenzae (Haemophilus influenzae), Bacillus anthracis, Mycoplasma pneumoniae, Moraxella catarralis, Chlamydia pneumoniae, Legionella pneumophila ), Mycobacterium tuberculosis, Staphylococcus epidermidis or secluded Monotherapy for the prevention and treatment of bacterial infections caused by Helicobacter pylori. Typically, the pharmaceutical compositions of the invention will be administered from about 1 to 5 times per day or alternatively, for continuous infusion. Or, alternatively, the composition of the invention may

O:\90\90896.DOC -56- 1334416 脈動調配物投予。該投予可作為慢性或急性治療使用。可 與載體物質合併產生單—劑型之活性成分的量將視欲治療 之宿主和投予之特定模態而改變。典型製劑將包含從約5% 到約95%之活性化合物（w/w)。較佳，該等製冑包含從約鳩 到約80%之活性化合物。 當本發明組合物包含式㈤化合物和—或多種額外治療 或預防藥劑的組合物時，化合物和額外藥劑二者都應以單 一治療之正常投予劑量的約丨〇%到8〇%之劑量含量存在。 -旦病人情況的改善’可投予本發明化合物、組合物或 組合物的一維持劑量’如果必需。其後，投予的劑量或頻 率’或兩者，可被減少（以症狀的函數）到維持改善情況的含 量，當症狀已減輕到所要程度時’應停止治療。然而，病 人在長期基礎上一旦任何再現或疾病症狀時，需要間歇治 療0 如熟習該項技術者應知的，可能需要低於或高於所列的 劑量。任何制病人的特殊劑量和治療㈣法將視多種因 素’包括所㈣定化合物的活性、年齡、豸重、_般健康 狀態、性別、日常飲食、投予時間、排泄的料、㈣组 合、疾病的嚴重性和期間及病人對疾病的素質和治療醫師 的裁判而定。 視特定情況，或欲治療或預防之疾病而定，額外治療劑， 其-般投予以治療或預防情況，也可出現在本發明組合物 中。如使用在此處中般投予以治療或預防特定疾病或情 況的額外治療劑’知道為，，適用於欲治療之疾病，或产況”。O:\90\90896.DOC -56- 1334416 Pulsating formulations were administered. This administration can be used as a chronic or acute treatment. The amount of active ingredient which may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to be treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Preferably, the oxime comprises from about 鸠 to about 80% of the active compound. When a composition of the invention comprises a composition of a compound of formula (5) and/or a plurality of additional therapeutic or prophylactic agents, both the compound and the additional agent should be administered in a dosage of from about 丨〇% to about 8% of the normal dosage of a single treatment. The content is present. - Improved patient condition 'A maintenance dose can be administered to a compound, composition or composition of the invention' if necessary. Thereafter, the dose or frequency of administration, or both, can be reduced (as a function of symptoms) to the level of maintenance improvement, and should be discontinued when the symptoms have been alleviated to the desired extent. However, patients who require any intermittent or disease symptoms on a long-term basis require intermittent treatment. 0 Those who are familiar with the technique may need to be below or above the listed dose. The special dose and treatment (4) method for any patient will depend on a variety of factors 'including the activity of the compound (4), age, weight, _ general health status, gender, daily diet, time of administration, excretion, (4) combination, disease The severity and duration of the patient and the quality of the disease and the judgment of the treating physician. Depending on the particular circumstances, or the condition to be treated or prevented, additional therapeutic agents, which are generally administered for treatment or prevention, may also be present in the compositions of the present invention. If an additional therapeutic agent is used to treat or prevent a particular disease or condition as described herein, it is known to be applicable to the disease to be treated, or the condition of the condition.

OA9OV90896.DOC -57- 1334416 該等藥劑包括（但不限制於）抗生素、抗發炎劑、基質金屬蛋 白酶抑制劑'脂肪氧合囲抑制劑、細胞激素拮抗劑、免疫 抑制劑、抗癌劑、抗病毒劑、細胞激素、生長因子、免疫 調節劑、前列腺素 '抗血管增生化合物或增加細菌生物對 抗生素的敏感性之藥劑。 增加細菌生物對抗生素的敏感性之藥劑為已知的。例 如，美國專利第5,523,288號、美國專利第5,783,561號及美 國專利第6，140,306號揭述使用殺菌劑/滲透性_增加的蛋白 質（BPI)以增加葛蘭氏陽性和葛蘭氏陰性細菌的抗生素敏 感性之方法。增加細菌生物之外膜浸透性的藥劑已由 Vaara’ M.描述在微生物綜覽（1992)第395-411頁中，和葛蘭 氏陰性細菌的致敏作用已被Tsubery，H.等人描述在j.Med Chem· (2000)第 3085-3092頁中。 根據另一具體實施例，本發明提供一種治療或減少病人 之細菌感染的嚴重性之方法，其包含將根據本發明之組合 物投予至該病人之步驟。 根據另一具體實施例，本發明提供一種在生物樣品中抑 制促旋酶之方法。 根據另一具體實施例，本發明提供一種在生物樣品中抑 制Topo IV之方法。 據另具體貫施例’本發明提供一種減少生物樣品中 的細囷量之方法。 根據另—具體實施例’本發明提供一種減少生物樣品中 的、、田菌里之方法，但尚包含使該生物樣品與一種增加細菌OA9OV90896.DOC -57- 1334416 These agents include, but are not limited to, antibiotics, anti-inflammatory agents, matrix metalloproteinase inhibitors, lipoxygenation inhibitors, cytokine antagonists, immunosuppressants, anticancer agents, antibiotics Viral agents, cytokines, growth factors, immunomodulators, prostaglandins' anti-angiogenic compounds or agents that increase the sensitivity of bacterial organisms to antibiotics. Agents that increase the sensitivity of bacterial organisms to antibiotics are known. For example, U.S. Patent No. 5,523,288, U.S. Patent No. 5,783,561, and U.S. Patent No. 6,140,306 disclose the use of bactericide/permeability-increased protein (BPI) to increase antibiotics of Gram-positive and Gram-negative bacteria. The method of sensitivity. Agents that increase the membrane permeability of bacterial organisms have been described by Vaara' M. in the Microbiology Overview (1992) pp. 395-411, and the sensitization of Gram-negative bacteria has been described by Tsubery, H. et al. In j.Med Chem. (2000), pp. 3085-3092. According to another specific embodiment, the invention provides a method of treating or reducing the severity of a bacterial infection in a patient comprising the step of administering a composition according to the invention to the patient. According to another specific embodiment, the invention provides a method of inhibiting gyrase in a biological sample. According to another specific embodiment, the invention provides a method of inhibiting Topo IV in a biological sample. According to another embodiment, the present invention provides a method of reducing the amount of fine mash in a biological sample. According to another embodiment, the present invention provides a method for reducing the amount of bacteria in a biological sample, but still includes the biological sample and an increased bacteria.

O:\90\9O896.DOC -58- 1334416 生物對抗生素之敏感性的藥劑接觸的步驟。 本發明之醫藥組合物和方法通常可用於控制活體内的細 菌感染。可被本發明組合物和方法控制的細菌生物之例子 包括（但不限制於）下列生物：肺炎雙球菌（streptococcus pneumoniae)、曝膿鍵球菌（streptococcus pyogenes)、糞腸球菌 (Enterococcus faecalis)、腸球菌（Enterococcus faecium)、克雷 白氏肺炎桿菌（Klebsiella pneumoniae)、腸細菌屬（Enterobacter sps.)、變形桿菌屬（Proteus sps.)、綠膿桿菌、大桿腸菌、黏 質沙雷氏菌（Serratia marcesens)、金黃色葡萄球菌、Coag. Neg. Staph、流感嗜血桿菌（Haemophilus influenzae)、炭疽桿菌 (Bacillus anthracis)、肺炎徽漿菌（Mycoplasma pneumoniae)、莫 拉斯氏菌屬（Moraxella catarralis)、流感嗜血桿菌（Η. influenzae)、肺炎披衣菌（Chlamydia pneumoniae)、嗜肺性退伍 軍人桿菌（Legionella pneumophila)、結核分枝桿菌 (Mycobacterium tuberculosis)、幽門螺旋桿菌（Helicobacter pylori)、表皮葡萄球菌（Staphylococcus epidermidis)、肺炎披 衣菌（Chlamydia pneumoniae)、嗜肺性退伍軍人桿菌 (Legionella pneumophila)、結核分枝桿菌（Mycobacterium tuberculosis)或Helibacter pylori。 該等組合物和方法將因此可用於控制、治療或減少醫院 或非醫院感染的進展、嚴重性或效果。醫院使用的例子包 括（但不限制於）尿道感染，呼吸器官感染例如肺炎，外科創 傷感染，和血流感染（也已知為菌血症）。非醫院使用的例子 包括（但不限制於）尿道感染、肺炎、前列腺炎、皮膚或軟組 O:\90\90896.DOC •59· 1334416 織感染、腹内感染及熱性嗜中 病人的治療。 f·生白血球減少（neutr〇penic) 術語".醫藥上有效量”係指有 之罝。術語”預防有效量"係指 細菌感染之量。 效治療或改善病人細菌感染 有效預防或實質上減少病人 =化合物可以控制活體内細菌感染含量和治療疾病 或減少由細菌媒介之效果的進展或嚴重性之習知方式使 =該等m療的方法，其劑量含量和需求可由該等熟習該 項技術者從有使用之方法和技術中選擇。 例如：本發明的化合物可與醫藥上可接受的佐劑合併， 用：醫樂上可接受的方式和有效減少感染或疾病的嚴重性 之里投予至患有細菌感染或疾病之病人。 或者’本發明的化合物可传 便·用於延長時間治療或防止個 人細菌感染或疾病的組合物戎方、、表儿人* 口物玖方去。化合物可單獨或與本 I明之其他化合物·-起以赫诚$* * 4/ 交Μ根據酵素抑制劑在醫藥組合物中 之習知利用的方式使用於兮笪έ人* 、m %忑寺組合物中。例如，本發明的 化口物可與習用於疫苗之醫藥上可接受的佐劑合併且以預 防有效量投予以經過延長時間之抗細菌感染或疾病而保護 個體。 式I的化合物也可與其他抗生素—起共投予以增加抗各 種細菌感染的治療或預防效果。當本發明的化合物以與其 他藥劑組合治療而投予時，他們可連續地或同時地投予至 病人。或者，根據本發明之醫藥或預防組合物包含式〗的化 合物和另外的治療或預防劑之組合物。O:\90\9O896.DOC -58- 1334416 The step of exposure of the agent to the sensitivity of the organism to antibiotics. The pharmaceutical compositions and methods of the present invention are generally useful for controlling bacterial infections in vivo. Examples of bacterial organisms that can be controlled by the compositions and methods of the invention include, but are not limited to, the following organisms: Streptococcus pneumoniae, streptococcus pyogenes, Enterococcus faecalis, intestines Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps., Proteus sps., Pseudomonas aeruginosa, E. coli, Serratia marcescens (Serratia marcesens), Staphylococcus aureus, Coag. Neg. Staph, Haemophilus influenzae, Bacillus anthracis, Mycoplasma pneumoniae, Moraxella catarralis ), Haemophilus influenzae (Η. influenzae), Chlamydia pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis, Helicobacter pylori, epidermis Staphylococcus epidermidis, Chlamydia pneum Oniae), Legionella pneumophila, Mycobacterium tuberculosis or Helibacter pylori. Such compositions and methods will therefore be useful for controlling, treating or reducing the progression, severity or effectiveness of a hospital or non-hospital infection. Examples of hospital use include, but are not limited to, urinary tract infections, respiratory infections such as pneumonia, surgical wound infections, and bloodstream infections (also known as bacteremia). Examples of non-hospital use include (but are not limited to) urinary tract infections, pneumonia, prostatitis, skin or soft groups O:\90\90896.DOC • 59· 1334416 Treatment of woven infections, intra-abdominal infections and patients with thermal hooliganism. f. White blood cell reduction (neutr〇penic) The term "pharmaceutically effective amount" means that the term "prophylactically effective amount" means the amount of bacterial infection. Effective treatment or improvement of bacterial infection in patients is effective in preventing or substantially reducing the number of patients = compounds can control the amount of bacterial infection in vivo and to treat diseases or reduce the progress or severity of the effects of bacterial vectors. The dosage levels and requirements may be selected by those skilled in the art from the methods and techniques employed. For example, a compound of the invention may be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from a bacterial infection or disease in a therapeutically acceptable manner and effective to reduce the severity of the infection or disease. Alternatively, the compound of the present invention can be used as a composition for prolonged treatment or prevention of bacterial infection or disease in a human, or as a human. The compound can be used alone or in combination with other compounds of the present invention, in accordance with the conventional use of the enzyme inhibitor in the pharmaceutical composition, in the manner of the use of the enzyme inhibitor in the pharmaceutical composition. In the composition. For example, the conjugate of the present invention can be combined with a pharmaceutically acceptable adjuvant conventionally used in vaccines and protected against prolonged anti-bacterial infections or diseases in a prophylactically effective amount. The compounds of formula I may also be co-administered with other antibiotics to increase the therapeutic or prophylactic effect against various bacterial infections. When the compounds of the present invention are administered in combination with other agents, they can be administered to the patient continuously or simultaneously. Alternatively, the pharmaceutical or prophylactic composition according to the invention comprises a combination of a compound of the formula and an additional therapeutic or prophylactic agent.

O:\90\90896.DOC •60- 1334416 上述額外治療劑可與含抑制劑之組合物分開地投予，以 夕劑里服用去。或者，這些藥劑可為與抑制劑混合成單一 組合物之單一劑型之部分。 ，了更完全了解本發明，陳述下列實例。這些實例僅為 了說明且以任何方式不解釋為限制本發明的範圍。 實例 貝丨上 、5-漠基_l，3-二氟基_2_石肖基苯：於5rc授掉下，經丄小時以 逐滴方式將4 -漠基-26 - ’· 一氟本胺在乙酸（10毫升）中的溶液 加到過棚酸鈉四水合物（1.〇4克，5毫莫耳）在乙酸⑽毫升） 中的懸浮液。在5 5。(：下攪拌額外3小時之後，使溶液冷卻到 室溫和過濾'。缝倒進冰，及以乙酸乙料取兩次。合併 之有機萃取物以5 X 1 go毫升部分的水、鹽水連續地洗務， 乾燥（MgSQ4) ’和在真空中濃縮。所得殘餘物藉由在石夕凝膠 上以乙酸乙S旨：己烧（1 : 2G)溶離之管柱色層分析法純化以 提供780毫克之呈黃褐色@體的標題化合物。1hnmr 5 7.32(dt,2H)。 實例2 (✓臭基3氣基2_確基_苯基）_ih_p比嗤：口比。坐（η毫克， 1.05毫莫耳）在THF(1毫升）中的溶液加至氫化納（44毫克， 1.1毫莫耳，60%油分散）在彻(4毫升）中的在〇£&gt;c下授掉之 懸浮液。所得混合物在〇t下攪拌5分鐘及加入5·溴基]，3_ 二敗基-2-确’基苯（238毫克’ i毫莫耳心师毫升）中的溶 液。混合物在室溫下授拌i小時，藉由加水（1毫升）停止反O:\90\90896.DOC • 60- 1334416 The above additional therapeutic agent can be administered separately from the composition containing the inhibitor, and taken in the evening. Alternatively, these agents may be part of a single dosage form that is combined with the inhibitor into a single composition. For a fuller understanding of the invention, the following examples are set forth. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way. Example: B. sulphate, 5- lysyl _l,3-difluoro-based 2- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A solution in acetic acid (10 ml) was added to a suspension of sodium persaltrate tetrahydrate (1. 4 g, 5 mmol) in acetic acid (10 ml). At 5 5 . (: After stirring for an additional 3 hours, the solution was allowed to cool to room temperature and filtered.) Sewed into ice and taken twice with acetic acid. The combined organic extracts were continuously 5 x 1 go ml of water, brine. Washing, drying (MgSQ4)' and concentrating in vacuo. The residue obtained was purified by column chromatography on EtOAc EtOAc: EtOAc (1:2G). </ br> </ br> </ br> </ br> Milliol) solution in THF (1 ml) was added to a suspension of sodium hydride (44 mg, 1.1 mmol, 60% oil dispersion) in EtOAc (4 mL). The resulting mixture was stirred at 〇t for 5 minutes and a solution of 5· bromo], 3 bis succinyl-2- benzene (238 mg 'i millimolar milliliters) was added. The mixture was at room temperature. Mix it for 1 hour, stop by adding water (1 ml)

O:\90\90896.DOC -61 · 1334416 應，然後分溶在水（20毫升）和乙酸乙酯（5〇毫升）之間。有機 層以鹽水洗滌，乾燥（MgS〇4)，和在真空中濃縮。殘餘物藉 由管柱色層分析法在矽凝膠上以乙酸乙酯：己烷（1:6)溶離 屯化以^供240宅克（86%)的標題化合物。ljj nmr (cdc13) 占 6.55 (t，1H)，7.45 (d，1H)，7.60 (S，1H)，7.80 (m，2H)。Ms 刪取 M+l+2 289 〇 實例3 5-溴基-2-硝基-3-吡唑-1-基-苯胺：氨（3毫升，在甲醇中 的2N)加至1_(5_溴基_3_氟基_2_硝基_苯基）_lH•吡唑p的毫 克，0,84毫莫耳）在乙醇（3毫升）中的溶液。所得混合物在密 封管中於8(TC下加熱16小時然後在真空中濃縮。殘餘物藉 由管柱色層分析法在矽凝膠上以乙酸乙酯：己烷（1:3)溶離 純化以提供205毫克（86%)之黃色固體的標題化合物。1h NMR (CDCI3) ^ 5.20 (br s, 2H), 6.50 (t, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.7 (d，1H)，7.8 (d，1H)。MS M+l 283, M+l+2 285。 實例4 2-硝基-3-吡唑_1-基-5-吡啶_3_基-苯胺^ 5·溴基_2_硝基-% 吡唑-1-基-苯胺（200毫克，〇·71毫莫耳）在THF(8毫升）中的溶 液内連續地加入3-吡啶基-二乙基硼烷（157毫克）、（肆三苯 基膦）鈀（0)(84毫克）和碳酸鈉（1」毫升，2 2mm〇mi2M水溶 液）。所得混合物在70°C攪拌過夜然後冷卻到室溫。反應混 合物以乙酸乙酯（100毫升）稀釋和以水（5〇毫升）、鹽水（5〇毫 升）洗滌，乾燥（MgSOJ然後在真空中濃縮。所得殘餘物藉 由管柱色層分析法在石夕凝膠上以乙酸乙酯：己炫（1: 3，^ .O:\90\90896.DOC -61 · 1334416 should then be partitioned between water (20 ml) and ethyl acetate (5 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:hexanes (1:6) to afford 240% (86%) of the title compound. Ljj nmr (cdc13) occupies 6.55 (t, 1H), 7.45 (d, 1H), 7.60 (S, 1H), 7.80 (m, 2H). Ms deleted M+l+2 289 〇 Example 3 5-Bromo-2-nitro-3-pyrazol-1-yl-phenylamine: Ammonia (3 ml, 2N in methanol) was added to 1_(5_ A solution of bromo-3-fluoro-2-nitro-phenyl)-lH-pyrazole p in mg, 0,84 mmol (m.) in ethanol (3 mL). The resulting mixture was heated in a sealed tube at 8 (TC) for 16 hours and then concentrated in vacuo. The residue was purified by column chromatography chromatography eluting with ethyl acetate:hexane (1:3) The title compound is 205 mg (86%) of yyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy (d,1H), 7.8 (d,1H). MS M+l 283, M+l+2 285. Example 4 2-nitro-3-pyrazol-1 -yl-5-pyridine-3-yl- Anthracene 5·bromo-2-nitro-% pyrazol-1-yl-phenylamine (200 mg, 〇71 mmol) was added continuously to a solution of 3-pyridyl in THF (8 mL). Diethylborane (157 mg), (p-triphenylphosphine)palladium(0) (84 mg) and sodium carbonate (1 mL, 2 2 mm 〇mi 2 M aqueous solution). The mixture was stirred at 70 ° C overnight and then cooled. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Analytical method on the Shixi gel with ethyl acetate: hex (1: 3, ^.

O:\9O\90896.DOC •62· 1334416 2，1 : 〇，2 : 1，4 : 1，8 : 1)的梯度溶離純化，以提供120 毫克（60%)黃色固體的標題化合物。iHNMR(DMS〇_d6)占6.45 (br,s 2H), 6.55 (t, 1H), 7.1 (s, 1H), 7.25 (s} 1H), 7.55 (m, 1H), 7.7 (s, 1H), 8.1 (dt，1H)，8.3 (d, 1H), 8.7 (d，1H)，8.9 (s，1H)。 實例5 1-乙基-3-(7_吡唑_l-基_5_吡啶苯并咪唑_2_基）_ 月尿（1-2): 2-；6肖基-3-叶坐-1-基-5-P比。定-3-基-苯胺（120毫克， 0.40毫莫耳）和10%鈀/碳（12毫克）在乙酸乙酯（1()毫升）中的 懸浮液放置在45 psi的氫壓下的Parr氫化器中。混合物震盪 16小時’過濾和在真空中濃縮濾液。所得殘餘物以 H2S〇4(1.6毫升或1 N)稀釋，且加入ν’-乙基-N-氰基脲（〇.8毫 升，1 Μ)。混合物在95 C下加熱4小時然後在真空中濃縮。 殘餘物藉由製備級HPLC純化以提供75毫克呈雙_丁从鹽的 標題化合物，其被轉化成游離鹼以提供標題化合物。ljiNMR (DMSO-d6) δ 1.1 (t, 3H), 3.2 (m, 2H), 7.0 (m, 1H), 7.3 (d, 1H), 7.5 (m, 1H), 7.55 (s, 1H), 8.0 (d, 1H), 8.55 (dd, 1H), 8.85 (s, 1H), 10.1 (s, 1H), 12.0 (s, 1H). LC/MS—個峰 ’ M+l 348.23, M-l 346.18。 貫例6 Ν’-乙基-N-氰基脲：胺基氰（8.5克，202.25毫莫耳）然後異 氰酸乙酯（4毫升，50.56毫莫耳）以逐滴方式經1〇分鐘加至氫 氧化鈉的20°C溶液中（1·5 Μ水溶液，50毫升，75 〇2毫莫 耳）。在攪拌30分鐘之後，加入額外氫氧化鈉（3Μ, 25毫升， 75.02¾莫耳）和異氰酸乙酯（4毫升，50.56毫莫耳ρ然後所 得溶液在直接地使用之前老化30分鐘之最小量而沒有離 O:\90\90896.DOC -63- 1334416 析。 實例7 4-〇比。定-3-基）-2-硝基苯胺：吡啶_3_賴酸丨，3_丙二醇環酯 (4克’ 24毫莫耳）、碳酸氫鈉（45毫升，1 μ)和肆（三苯基膦） 鈀（〇·〇5當量）加至4-溴基-2-硝基苯胺（4.8克，22毫莫耳）在 DME( 100耄升）中的溶液。所得混合物在下加熱8小時 然後冷卻到室溫。收集該等固體，以水、在己烷中的5〇/〇 EtOAc洗滌和乾燥以提供標題化合物（5克）。iH (CDCl3) δ 8.8 (d, 1H), 8.55 (m, 1H), 8.35 (d, 1H), 7.85 (dd, 1H), 7.65 (dd, 1H), 7.35 (m，1H)，6.95 (d，1H)，6.25 (br s，2Ii)。 實例8 2-溴基-6-硝基4-吡啶-3-基-苯胺：在HOAcP毫升）中的 溴（1.58克，9.9毫莫耳）加至4-(吡啶-3-基）-2-硝基苯胺（1.3 克，9毫莫耳）在HOAc(25毫升）中的溶液。所得混合物在室 溫下攪拌一小時和然後以冰-水停止反應。收集該等固體， 以水洗滌和乾燥。在EtOAc中的固體然後以Na〇H(2N ; 20 毫升）、水、鹽水洗滌和在真空中濃縮。濃縮物藉由色層分 析法[矽凝膠’乙酸乙酯：己烷（1 : 1)]純化以提供標題化合 物（0.8克）。丨HNMR(CDC13) 5 8.83(d，lH)，8.55(m，lH)，8_41(d，lH)， 8-15 (d, 1H), 7.96 (m, 1H), 7.41 (m, 1H), 6.80 (br s, 2H). (M+l) 294 〇 實例9 2-硝基-6-吡啶-2-基-4-吡啶-3-基-苯胺：2·溴基_6_硝基_4_ p比唆-3-基-苯胺（100毫克，1當量），2-p比咬基溴化辞（6當量） 和肆（三苯基膦）鈀（0.1當量）在THF(10毫升）中的混合物在 O:\M\90S96.DOC -64- 1334416 1 〇〇 °C下加熱18小時。反應以水（2毫升 J 1了止。產物以O.\9O\90896.DOC • 62· 1334416 2,1: 〇, 2:1, 4:1,8:1). iHNMR(DMS〇_d6) occupies 6.45 (br,s 2H), 6.55 (t, 1H), 7.1 (s, 1H), 7.25 (s} 1H), 7.55 (m, 1H), 7.7 (s, 1H) , 8.1 (dt, 1H), 8.3 (d, 1H), 8.7 (d, 1H), 8.9 (s, 1H). Example 5 1-Ethyl-3-(7-pyrazole-1-yl-5-pyridinebenzimidazole_2-yl)_ Moon urine (1-2): 2-;6 肖基-3-叶坐-1-yl-5-P ratio. A suspension of dec-3-yl-aniline (120 mg, 0.40 mmol) and 10% palladium on carbon (12 mg) in ethyl acetate (1 mL) was placed under a hydrogen pressure of 45 psi. In the hydrogenator. The mixture was shaken for 16 hours&apos; filtered and the filtrate was concentrated in vacuo. The residue obtained was diluted with H2S 4 (1.6 mL or 1 N), and ν'-ethyl-N-cyanourea ( 〇. The mixture was heated at 95 C for 4 hours and then concentrated in vacuo. The residue was purified by preparative EtOAc EtOAc (EtOAc) LjiNMR (DMSO-d6) δ 1.1 (t, 3H), 3.2 (m, 2H), 7.0 (m, 1H), 7.3 (d, 1H), 7.5 (m, 1H), 7.55 (s, 1H), 8.0 (d, 1H), 8.55 (dd, 1H), 8.85 (s, 1H), 10.1 (s, 1H), 12.0 (s, 1H). LC/MS—peaks M+l 348.23, Ml 346.18. Example 6 Ν'-Ethyl-N-cyanourea: Amino cyanide (8.5 g, 202.25 mmol) followed by ethyl isocyanate (4 mL, 50.56 mmol) in 1 minute by drop Add to a solution of sodium hydroxide in 20 ° C (1. 5 Μ aqueous solution, 50 ml, 75 〇 2 mmol). After stirring for 30 minutes, additional sodium hydroxide (3 Torr, 25 ml, 75. 012⁄4 mol) and ethyl isocyanate (4 ml, 50.56 mmol) were added and the resulting solution was aged for 30 minutes before being used directly. The amount is not separated from O:\90\90896.DOC -63- 1334416. Example 7 4-〇 ratio. D--3-yl)-2-nitroaniline: pyridine _3_ lysine sulphate, 3- propylene glycol ring Ester (4 g '24 mmol), sodium bicarbonate (45 ml, 1 μ) and hydrazine (triphenylphosphine) palladium (〇·〇 5 equivalents) were added to 4-bromo-2-nitroaniline ( 4.8 g, 22 mmol) solution in DME (100 liters). The resulting mixture was heated under 8 hours and then cooled to room temperature. The solid was collected, washed with EtOAc EtOAc EtOAc EtOAc iH (CDCl3) δ 8.8 (d, 1H), 8.55 (m, 1H), 8.35 (d, 1H), 7.85 (dd, 1H), 7.65 (dd, 1H), 7.35 (m,1H), 6.95 (d , 1H), 6.25 (br s, 2Ii). Example 8 2-Bromo-6-nitro-4-pyridin-3-yl-phenylamine: Bromine (1.58 g, 9.9 mmol) in HOAcP mL) was added to 4-(pyridin-3-yl)-2 A solution of 1-nitroaniline (1.3 g, 9 mmol) in HOAc (25 mL). The resulting mixture was stirred at room temperature for one hour and then quenched with ice-water. The solids were collected, washed with water and dried. The solid was washed with EtOAc (EtOAc)EtOAc. The concentrate was purified by EtOAc (EtOAc: EtOAc:EtOAc)丨HNMR(CDC13) 5 8.83(d,lH), 8.55 (m,lH),8_41(d,lH), 8-15 (d, 1H), 7.96 (m, 1H), 7.41 (m, 1H), 6.80 (br s, 2H). (M+l) 294 〇 Example 9 2-Nitro-6-pyridin-2-yl-4-pyridin-3-yl-phenylamine: 2·Bromo-6-nitro- 4_p is indole-3-yl-phenylamine (100 mg, 1 equivalent), 2-p ratio bromine (6 equivalents) and hydrazine (triphenylphosphine) palladium (0.1 equivalents) in THF (10 ml) The mixture was heated at O:\M\90S96.DOC-64-1334416 1 〇〇 °C for 18 hours. The reaction was stopped with water (2 ml of J 1 .

Et〇Ac(2()x3)萃取。然後在真空中濃縮合併之有機層和殘餘 物藉由色層分析法（矽凝膠，EtOAC)純化以提供黃色固體的 標題化合物（75毫克）。（M+l)293。 實例10 3-吡啶-2-基-5-峨咬-3-基-苯-1，2_二胺：1〇%紐/碳（5〇毫克） 加到2-硝基-6-吡啶-2-基-4_吡啶_3_基-苯胺（75毫克，〇 %毫 莫耳）在乙酸乙酯（20毫升）中的溶液。所得懸浮液放置在4〇 psi氫氣下之Parr氫化設備中同時在室溫搖動一小時。過濾 除去催化劑和在真空中濃縮濾液以提供化合物標題化合^ (50毫克，0.19毫莫耳）。 實例11 1-乙基-3-(7-吡啶-2-基-5-吡啶-3-基-1H-苯并咪唑_2_基）_ 腿（1-31): N··乙基氰基脲（0.76毫升，1M)加到弘吡咬^ 基-5-吡啶-3-基-苯-1，2-二胺（5〇亳克，〇 19毫莫耳）和硫酸 (0.76宅升，1N)在水（1毫升）中的溶液。逐滴加入足夠的硫 酸以達成pH 3。所得混合物在1〇〇°c下加熱8小時。反應混 合物然後冷卻到室溫。收集該等固體，以水洗滌和乾燥。 該等固體藉由色層分析法（矽凝膠，Et〇Ac，然後在Et〇Ac 中之10% MeOH)純化以提供化合物5(27毫克）。ihnmr(CDCl3) δ 8.92 (d, 1H), 8,80 (m, 1H), 8.52 (m, 1H), 8,30 (m, 1H), 8.21 (d, 1H), 8.04 (s, 1 H), 7.94 (m, 1H), 7.75 (s, 1H), 7.56 (d5 1H), 7.37 (m, 2H), 3.36 (q, 2H), 1.24 (t, 3H)。（M+l) 359。 實例12 0：\90\90896.D〇C •65- 1334416Et〇Ac(2()x3) extraction. The combined organic layer was purified by EtOAcqqqqqqqq (M+l) 293. Example 10 3-Pyridin-2-yl-5-indole-3-yl-benzene-1,2-diamine: 1% neon/carbon (5 mg) added to 2-nitro-6-pyridine- A solution of 2-yl-4-pyridine-3-yl-aniline (75 mg, 〇% mmol) in ethyl acetate (20 mL). The resulting suspension was placed in a Parr hydrogenation apparatus under 4 psi of hydrogen while shaking at room temperature for one hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford titled compound (50 mg, 0.19 m). Example 11 1-Ethyl-3-(7-pyridin-2-yl-5-pyridin-3-yl-1H-benzimidazole_2-yl)_ leg (1-31): N··ethyl cyanide The base urea (0.76 ml, 1 M) was added to the chlorpyrifos-5-pyridin-3-yl-benzene-1,2-diamine (5 gram, 〇19 mmol) and sulfuric acid (0.76 liter) , 1N) a solution in water (1 ml). Sufficient sulfuric acid is added dropwise to achieve a pH of 3. The resulting mixture was heated at 1 ° C for 8 hours. The reaction mixture was then cooled to room temperature. The solids were collected, washed with water and dried. The solids were purified by chromatography (EtOAc, EtOAc (EtOAc:EtOAc) Ihnmr(CDCl3) δ 8.92 (d, 1H), 8,80 (m, 1H), 8.52 (m, 1H), 8,30 (m, 1H), 8.21 (d, 1H), 8.04 (s, 1 H ), 7.94 (m, 1H), 7.75 (s, 1H), 7.56 (d5 1H), 7.37 (m, 2H), 3.36 (q, 2H), 1.24 (t, 3H). (M+l) 359. Example 12 0:\90\90896.D〇C •65- 1334416

2,2-二曱基-N-(2-嘧啶-2-基-苯基）-丙醯胺：5升燒瓶中進 料呈四水合物之上述蝴酸（281.4克，960毫莫耳）、2-氣嘧啶 -(100 克，874 毫莫耳）、NaHC03( 146.8 克，1.746 莫耳）和 卩&lt;1(??113)4(10.0克，8.72毫莫耳）。加水（1升）和二甲氧基乙烷 (1升），及混合物慢慢地加熱到83°C (内溫）經1小時並高架攪 拌。在〜2小時之後所有的固體溶解。使反應攪拌8小時。混 合物冷卻到室溫且在攪拌過夜，之後稠沈澱物形成。粗混 合物以水（2升）稀釋且攪拌額外2個小時，之後過濾混合物和 該等固體再次以水、0. IN NaOH和水連續地洗滌。然後在 高真空下於50°C乾燥固體以提供黃褐色粉末的標題化合物 (〜233克）。 實例132,2-Dimercapto-N-(2-pyrimidin-2-yl-phenyl)-propanamide: The above-mentioned fosic acid (281.4 g, 960 mmol) fed as a tetrahydrate in a 5 liter flask. 2-pyrimidine-(100 g, 874 mmol), NaHC03 (146.8 g, 1.746 mol) and 卩&lt;1 (??113) 4 (10.0 g, 8.72 mmol). Water (1 L) and dimethoxyethane (1 L) were added, and the mixture was slowly heated to 83 ° C (internal temperature) over 1 hour and stirred overnight. All solids dissolved after ~2 hours. The reaction was allowed to stir for 8 hours. The mixture was cooled to room temperature and stirred overnight before a thick precipitate formed. The crude mixture was diluted with water (2 L) and stirred for an additional 2 hours, after which time the mixture was filtered and the solids were washed again with water, &lt;RTIgt; The solid was then dried under high vacuum at 50 &lt;0&gt;C to afford the title compound (~ 233 g). Example 13

1) Br2/HOAc/RT 2) 以水停止反應/Na2S2〇31) Br2/HOAc/RT 2) Stop the reaction with water / Na2S2〇3

3) Br2/HOAc/RT 4) 以水停止反應/Na2S2033) Br2/HOAc/RT 4) Stop the reaction with water / Na2S203

N - ( 4 - &gt;臭基-2 -喷α定-2 -基-苯基）-2，2 -二甲基-丙酸胺.經1小 時週期將溴（67毫升，1.31莫耳）在100毫升乙酸中的溶液加 到2,2-二甲基-；^-(2-嘧啶-2-基-苯基）-丙醯胺（~117克，43 7毫 莫耳）在乙酸（1升）中的室溫懸浮液。不均混合物在室溫下攪 拌5個小時，整個時間形成的稠沈澱物。混合物然後倒進冰 O:\90\90896.DOC -66- 1334416 中’以1 N Na2S2〇3(2升）稀釋，和攪拌1小時。過濾該等固 體’再懸浮於水（2升）中，攪拌1小時，然後過濾和再次以水 洗滌。所得固體於50°C下抽氣到乾，再懸浮於HOAc(l升） 中，和用在溴（22毫升430毫莫耳）在乙酸溶液（20毫升）中處 理20分鐘。攪拌所得不均混合物5小時，然後停止反應和如 上所述處理。所得固體於5〇。〇下真空乾燥以提供黃褐色粉 末的標題化合物（165克）。 實例14N - ( 4 - &gt; odorant-2 - oxadine - 2 - phenyl-phenyl)-2,2-dimethyl-propionic acid amine. Bromine (67 ml, 1.31 mol) over 1 hour period A solution in 100 ml of acetic acid was added to 2,2-dimethyl-;^-(2-pyrimidin-2-yl-phenyl)-propanamide (~117 g, 43 7 mmol) in acetic acid ( Room temperature suspension in 1 liter). The heterogeneous mixture was stirred at room temperature for 5 hours to form a thick precipitate over time. The mixture was then poured into ice O:\90\90896.DOC -66- 1334416 and diluted with 1 N Na2S2〇3 (2 liters) and stirred for 1 hour. The solids were filtered and resuspended in water (2 liters), stirred for 1 hour, then filtered and washed again with water. The resulting solid was evacuated to dryness at 50 ° C, resuspended in HOAc (1 liter) and treated in bromo (22 mL 430 mM) in acetic acid (20 mL) for 20 min. The resulting heterogeneous mixture was stirred for 5 hours, then the reaction was stopped and treated as described above. The resulting solid was at 5 Torr. The title compound (165 g) was obtained as a yellow brown powder. Example 14

N-(4-溴基-2-硝基-6-嘧啶-2-基-苯基）-2,2-二甲基-丙醯 胺：經30分鐘週期將90%硝酸（7〇毫升，146毫莫耳）加到 N-(4-溴基-2-嘧啶-2-基-苯基）-2,2-二曱基_丙醯胺（32.6克， 97_5毫莫耳）在TFA(400毫升）中的5。〇懸浮液。然後使混合物 加溫到室溫和攪拌總計2個小時。粗反應（現為均勻）倒進冰 中而產生糊狀塊。混合物以水稀釋到2升的總體積，以5〇〇 毫升的甲醇處理，和激烈攪拌12小時。過濾所得固體，以 很多的水洗滌，然後於5(TC下真空乾燥以提供黃揭色粉末 的標題化合物（29.9克，81%產率）。 實例1 5 O:\90\90896.DOC •67· 1334416N-(4-bromo-2-nitro-6-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propanamide: 90% nitric acid (7 mL) over a 30 minute period. 146 mmol) was added to N-(4-bromo-2-pyrimidin-2-yl-phenyl)-2,2-diindenyl-propionamide (32.6 g, 97_5 mmol) in TFA ( 5 of 400 ml). 〇 suspension. The mixture was then warmed to room temperature and stirred for a total of 2 hours. The coarse reaction (now homogeneous) is poured into the ice to produce a paste. The mixture was diluted with water to a total volume of 2 liters, treated with 5 mL of methanol, and stirred vigorously for 12 hours. The resulting solid was filtered, washed with EtOAc EtOAc EtOAc (EtOAc) · 1334416

4-溴基-2-硝基-6-嘧啶-2-基-苯胺：將N_(4_溴基硝基_6 嘧啶-2-基-苯基）-2,2-二曱基-丙醯胺（29.9克，78.8毫莫耳） 在濃HC1(200毫升）中的懸浮液回流8小時。然後將部份均勻 的粗反應冷卻到室溫，以水（500毫升）稀釋，和所得沈澱物 攪拌1小時。然後過濾該等固體，以水洗滌，和於5〇。匸真办 下乾燥以k供橘色粉末的標題化合物（21.1克，91%產率） 實例164-bromo-2-nitro-6-pyrimidin-2-yl-aniline: N_(4-bromonitro-6-pyrimidin-2-yl-phenyl)-2,2-dimercapto-propyl The guanamine (29.9 g, 78.8 mmol) was refluxed for 8 hours in concentrated HCl (200 mL). Then, a part of the homogeneous crude reaction was cooled to room temperature, diluted with water (500 ml), and the obtained mixture was stirred for 1 hour. The solids were then filtered, washed with water, and at 5 Torr. The title compound (21.1 g, 91% yield).

2-硝基-6H2-基_4_(4,4,5,5_四甲基·π，3,2]二氧雜爛 烷（di〇xab_lan)-2-基）-苯胺：4_漠基_2_硝基心嘧啶_2基_ 苯胺（1.82克’ 6.2毫莫耳）、雙蘋那醇基（pinac〇iat^二％ (3-144 克 ’ 12.4 毫莫耳）、Pdci2dppf2(453 毫克，〇·6 毫莫耳） 和K〇Ac(3.03克，31毫莫耳）在二噚烷（6〇毫升）中的混合物在 l〇5°C下加熱2.5小時。過渡反應而且以二氣甲燒洗蘇。在 真空下濃縮合併的濾液，及將水（1〇〇毫升）加至殘餘物中。 以二氯曱烷（3x50毫升）萃取’乾燥和濃縮產生殘餘物，殘餘 物以醚-己烷洗滌以提供標題化合物（2 〇7克，98%)。 、 實例172-nitro-6H2-yl_4_(4,4,5,5-tetramethyl·π,3,2]dioxan (di〇xab_lan)-2-yl)-aniline: 4_Mo Base 2_nitrocardyrimidin-2-yl aniline (1.82 g '6.2 mmol), bisglycol (pinac〇iat^ two% (3-144 g ' 12.4 mmol), Pdci 2dppf 2 (453 Methanol, 〇·6 mM) and K〇Ac (3.03 g, 31 mmol) in a mixture of dioxane (6 mM) heated at l 〇 5 ° C for 2.5 hours. The gas was burned and the combined filtrate was concentrated under vacuum, and water (1 mL) was added to the residue. The mixture was extracted with dichloromethane (3×50 mL) and dried and concentrated to give a residue. The title compound (2 〇 7 g, 98%) was obtained eluted with ether-hexanes.

O:\90\9OS96.DOC -68· 1334416O:\90\9OS96.DOC -68· 1334416

N-[2-(3-氟基-吡啶-2-基）-苯基]-2,2-二甲基-丙醯胺：3升 燒瓶中進料呈四水合物之上述晒酸（92 ·丨克，3丨4毫莫耳）， 氣氟吡啶（37.6克，286毫莫耳）、NaHCO3(48.0克，572毫莫 耳）’和Pd(PPh3)4(3.3克，2.86毫莫耳）。加水（300毫升）和二 甲氧基乙烷（300毫升），及混合物慢慢地加熱到83。〔:（内溫） 經1小時並尚架攪拌。在〜2小時之後所有的固體溶解。使反 應攪拌10小時。混合物冷卻到室溫且在攪拌過夜，之後稠 膠狀物形成。粗混合物以水（2升）稀釋且攪拌額外2個小時。 然後使混合物休息而沒有攪拌直到膠狀物沈降到瓶底。藉 由真空除去液相，然後以G.l N NaOH替換且騎15分鐘。 使膠狀物沈降且經由真空除去液體。膠狀物然後以水同樣 地洗滌三次，然後轉移到一頸燒瓶作為丙輞溶液。混合物 在真空中濃縮和與乙酸乙酯共沸五次。 實例18N-[2-(3-Fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide: The above-mentioned tanning acid was fed as a tetrahydrate in a 3-liter flask (92). · gram, 3 丨 4 mM), fluoropyridine (37.6 g, 286 mmol), NaHCO3 (48.0 g, 572 mmol) and Pd (PPh3) 4 (3.3 g, 2.86 mmol) ). Water (300 ml) and dimethoxyethane (300 ml) were added, and the mixture was slowly heated to 83. [: (internal temperature) After 1 hour, it is still stirred. All solids dissolved after ~2 hours. The reaction was allowed to stir for 10 hours. The mixture was cooled to room temperature and stirred overnight, after which a thick gum formed. The crude mixture was diluted with water (2 L) and stirred for an additional 2 hours. The mixture was then allowed to rest without agitation until the gum settled to the bottom of the bottle. The liquid phase was removed by vacuum, then replaced with G.l N NaOH and allowed to ride for 15 minutes. The gum was allowed to settle and the liquid was removed via vacuum. The gum was then washed three times with water and then transferred to a one-necked flask as a propionate solution. The mixture was concentrated in vacuo and azeotroped five times with ethyl acetate. Example 18

BrBr

溴基_2_(3_敦基_七定_2基）_苯基]_2,2_二甲基-丙酿 臭（12毛升，228毫莫耳）在5〇毫升乙酸中之溶液經1小時 週期加到Ν-Γ2门g&gt; 12-(3-鼠基-吡啶_2_基）_苯基]_2,2·二甲基·丙醯A solution of bromo 2-(3-Denyl-ytidine-2-yl)-phenyl]_2,2-dimethyl-propene odor (12 mil, 228 mmol) in 5 mL of acetic acid The hourly period is added to Ν-Γ2 gate g&gt; 12-(3-muro-pyridin-2-yl)-phenyl]_2,2·dimethyl-propionamidine

O:\90\90896.DOC •69- 1334416 胺（77毫莫耳）在乙酸poo毫升）中的室溫懸浮液。不均混合 物在至酿下攪拌5小時，期間形成稠沈澱物。混合物然後倒 進冰中’以1 N NaAOWOO毫升）稀釋，和攪拌1小時。過 渡該等固體，再懸浮於水（2升）中，擾㈣、時，然後過渡和 再次以水洗滌。所得固體於5(rc下抽氣到乾，再懸浮於 H〇Ac(4〇〇毫升)中，和以之溴(4毫升，％毫莫耳)在乙酸溶 液（2〇毫升）中處理20分鐘。所得不均混合物攪拌5小時，然 後如上所述停止反應和處理。所得固體於5〇。亡下真空乾燥 以提供黃褐色粉末的標題化合物（191克，72。/〇)。 實例19O:\90\90896.DOC • 69- 1334416 A room temperature suspension of amine (77 mmol) in poo acetate. The heterogeneous mixture was stirred for 5 hours until it reached a thick precipitate. The mixture was then poured into ice and diluted with 1 N NaAOWOO mL, and stirred for 1 hour. The solids were transferred, resuspended in water (2 liters), disturbed (iv), then transitioned and washed again with water. The resulting solid was degassed to dryness at 5 (rc), resuspended in H.sub.sub.2Ac (4 mL) The resulting heterogeneous mixture was stirred for 5 hours, then quenched and treated as described above. The obtained solid was taken from EtOAc (EtOAc m.

N-[4-溴基-2-6-(3-氟基·吡啶_2-基）硝基苯基]_2,2_二甲基 -丙醯胺：於0°C，經45分鐘週期90%發煙硝酸（2.46毫升， 55.1毫莫耳）的TFA溶液（30毫升）加到N-[4-漠基- 2-(3 -說基_ p比咬-2-基）·苯基]-2,2-二甲基-丙醯胺（6.45克，18.4毫莫耳） 在TFA(l〇〇毫升）和TFAA(25.5毫升’ 183.6毫莫耳）中的懸浮 液。混合物然後於0°C下攪拌總計4小時。.粗反應（現為均勻） 倒進冰中而產生糊狀塊。混合物以水稀釋到5〇〇毫升總體 積’以50毫升的甲醇處理，和激烈地攪拌12小時。過遽所 得固體，以很多的水洗滌，然後在於50°C下真空乾燥以提 供黃褐色粉末的標題化合物（6.1克，82%產率）。 O:\90\90896.DOC -70- 1334416 實例20N-[4-Bromo-2-6-(3-fluoro-pyridin-2-yl)nitrophenyl]_2,2-dimethyl-propanamide: at 0 ° C over a 45 minute period 90% fuming nitric acid (2.46 ml, 55.1 mmol) in TFA solution (30 ml) was added to N-[4- lysyl-2-(3-sayy_p~bit-2-yl)·phenyl ]-2,2-Dimethyl-propanamide (6.45 g, 18.4 mmol) in a suspension of TFA (10 mL) and TFAA (25.5 mL '183.6 mmol). The mixture was then stirred at 0 ° C for a total of 4 hours. The coarse reaction (now homogeneous) is poured into the ice to produce a paste. The mixture was diluted with water to a total volume of 5 ml of water treated with 50 ml of methanol and vigorously stirred for 12 hours. The resulting solid was dried over EtOAc (EtOAc) elute O:\90\90896.DOC -70- 1334416 Example 20

2-(3,5-二氟基-苯基）-嘧啶：二氟麵酸（5.4克，34·!毫莫耳） 和2-氯嘧啶-(3.0克，26.2毫莫耳）在乙醇（5〇毫升）中的溶液 以 Na2C03(3.6 克，34_1 毫莫耳）和 Pd(PPh3)4(1.5 克，ι.31 毫莫 耳）處理然後在回流下加熱3天。所得混合物然後以Et〇Ac 稀釋，加入矽凝膠，和所得漿液在室溫下攪拌3小時。粗混 合物然後通過矽凝膠墊以Et〇Ac過濾，在真空中濃縮，和進 行急驟色層分析（矽凝膠，19/1_14/1_9/1_7/1己烷/Et〇Ac梯2-(3,5-Difluoro-phenyl)-pyrimidine: difluoro face acid (5.4 g, 34·! mmol) and 2-chloropyrimidine-(3.0 g, 26.2 mmol) in ethanol ( The solution in 5 ml) was treated with Na2C03 (3.6 g, 34_1 mmol) and Pd(PPh3) 4 (1.5 g, ι.31 mmol) and then heated under reflux for 3 days. The resulting mixture was then diluted with Et 〇Ac, a hydrazine gel was added, and the resulting syrup was stirred at room temperature for 3 hr. The crude mixture was then filtered through a ruthenium gel pad with Et 〇Ac, concentrated in vacuo, and subjected to flash chromatography (矽 gel, 19/1_14/1_9/1_7/1 hexane/Et〇Ac ladder)

度）以提供白色固體的標題化合物（丨3 8克，27%)。lH (dmso-d,, 500 MHz): 8.95 (d, 2H); 7.98 (m, 2H); 7.57 (dd, 1H); 7.48 (m5 1H)。 ’ 實例21The title compound (丨38 g, 27%) lH (dmso-d,, 500 MHz): 8.95 (d, 2H); 7.98 (m, 2H); 7.57 (dd, 1H); 7.48 (m5 1H).例 Example 21

2 (3’5_一氣基硝基-苯基）-喷啶：90% ΗΝΟ3(0·375毫 升9.37毫莫耳）經1〇秒經由注射器加到2_(3,5二氣基·笨 基）嘧疋（1.2克’6.24毫莫耳）在1128〇4(3毫升）中的室溫溶 所得此σ物在室溫下授拌i小時然後倒進冰内。所得不 均混合物然後以水蘇經 · &amp;稀釋’加溫到室溫，和過濾。該等固體 以水洗蘇和在直空φ於α 一工甲乾燥以提供黃褐色固體的標題化合物2 (3'5_mono-nitro-phenyl)-piperidine: 90% ΗΝΟ3 (0·375 ml 9.37 mmol) is added to the 2_(3,5 di-gas base) via a syringe for 1 〇 second The pyridinium (1.2 g '6.24 mmol) was dissolved in 1128 〇 4 (3 ml) at room temperature. The sigma was stirred at room temperature for 1 hour and then poured into ice. The resulting heterogeneous mixture was then warmed to room temperature with water sulphate &amp; dilution and filtered. The solids are washed with water and dried in a straight space φ at α-A to provide the title compound as a tan solid.

O:\90\90896.DOC -71 - 1334416 (1 ·53 克，1 00%)。NMR (dmso-de，500 MHz): 8.92 (d，2H); 8.67 (m， 1H); 7.94(m，1H); 7.65 (dd，1H)。 實例22O:\90\90896.DOC -71 - 1334416 (1 · 53 grams, 1 00%). NMR (dmso-de, 500 MHz): 8.92 (d, 2H); 8.67 (m, 1H); 7.94 (m, 1H); 7.65 (dd, 1H). Example 22

5-氟基-2-琐基-3·嘴u定·2-基-苯胺：在室溫下將 tBuNH2(6.6毫升’ 63.24毫莫耳）加到2_(3,5_二氟基_2_硝基苯 基）-¾°定（1.5克’ 6.32毫莫耳）在二p号烧（1〇毫升）中之溶液。 混合物在密封管中加熱到loot：經1〇小時。混合物然後冷卻 到室溫，倒進水内’和攪拌該等固體丨小時。過濾混合物， 以水洗蘇固體直到渡液透明。粗產物然後稀釋在Me〇H中， 加入6 N HC1 ’和所得混合物在回流下加熱3小時。反應冷 卻到室溫和倒進冰内。所得不均混合物加溫到室溫，過滤， 以水洗滌固體直到濾液透明’及在真空中乾燥以提供橘色 粉末的標題化合物（1.33 克 ’ 90%)。hNMR^dmsod&amp;SOOMHz): 8.87 (d，2H); 7.52 (dd，1H); 7.08 (dd，1H); 6.86 (dd, 1H); 6.60 (s，2H)。 實例235-Fluoro-2-zilyl-3. Methyl 2-aniline-aniline: tBuNH2 (6.6 ml '63.24 mmol) was added to 2_(3,5-difluoroyl_2 at room temperature) _Nitrophenyl) - 3⁄4 ° (1.5 g ' 6.32 mmol) in a solution of two p-fired (1 mL). The mixture was heated to a loot in a sealed tube: 1 hour. The mixture was then cooled to room temperature, poured into water&apos; and the solids were stirred for a few hours. The mixture was filtered and the solid was washed with water until the mixture was clear. The crude product was then diluted in Me 〇 H, 6 N HCl was added and the mixture obtained was heated under reflux for 3 hr. The reaction was cooled to room temperature and poured into ice. The resulting heterogeneous mixture was warmed to room temperature, filtered, and the solid was washed with water, and then filtered and evaporated to give the title compound (1.33 g &apos; 90%). hNMR^dmsod&amp;SOOMHz): 8.87 (d, 2H); 7.52 (dd, 1H); 7.08 (dd, 1H); 6.86 (dd, 1H); 6.60 (s, 2H). Example 23

1-(3-胺基-4-硝基-5-嘲咬-2-基-苯基〇坐-4-緩酸環 丙基醯胺：17(545毫克，3.6毫莫耳）和Na2C03(381毫克，3.60 1334416 毫莫耳）在室溫下加到5-氟基-2·硝基_3_^_2_基_笨胺（65〇 毫克，2.77毫莫耳）在DMF(5毫升）中的混合物。所得渡合物 加熱到1251經6小時’然後冷卻到室溫。所得混合物以水 稀釋’及將黃色沈殿物攪拌丨小時。過濾、粗反應和以水洗條 該等固體直到濾液透明。洗過的固體然後在真空中乾燥以 提供黃色粉末的標題化合物（960毫克，95%)。lHNMR(dms(Mi6, 500 MHz): 8.91 (d, 1H); 8.42 (s, 1H); 8.29 (Sj 1H); 8.08 (d, 1H); 7.52 (dd, 1H), 7.36 (d, 1H); 7.29 (d, 1H); 6.59 (s, 2H); 2.89 (m, 1H); .072 (m, 2H); 0.64 (m5 2H)= 實例241-(3-Amino-4-nitro-5-trinyl-2-yl-phenylindole-4-o-acid cyclopropyl decylamine: 17 (545 mg, 3.6 mmol) and Na2C03 ( 381 mg, 3.60 1334416 mmol, added to 5-fluoro-2,nitro-3_^2_yl-p-aminoamine (65 mg, 2.77 mmol) in DMF (5 mL) at room temperature The resulting mixture was heated to 1251 for 6 hours 'then cooled to room temperature. The resulting mixture was diluted with water' and the yellow sediment was stirred for a few hours. Filtration, crude reaction and washing of the solids with water until the filtrate was clear. The solid was then dried <RTI ID=0.0>(1 </RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (H, 1H); 7.52 (d, 1H); 7.29 (d, 1H); 6.59 (s, 2H); 2.89 (m, 1H); .072 (m, 2H); 0.64 (m5 2H)= Example 24

N’N-一乙基叛基-2 -甲基-2-硫假月尿：三乙胺（34_5毫升， 245.7毫莫耳）和氯曱酸乙酯（2〇.65克，245毫莫耳）加到2_甲 基-2-硫假脲琉酸g旨（22.8克，81 _9毫莫耳）在二氯甲烧（2〇〇毫 升）中的混合物。在攪拌過夜之後混合物以水、鹽水洗滌， 然後經過硫酸鈉乾燥，過濾和在真空縮濃至刺鼻的油狀 物’其進行急驟色層分析（1 0%乙酸乙酯/己烷）以提供無色 油狀物的標題化合物（16·68克，86.9% Y)，其靜置時固化。 iHNMR (500Mhz，CDC13) 5 1.3(q，6H)，2.41(s，3H)，4.22(m，4H)。 實例25N'N-Ethyl-Resin-2-methyl-2-sulfide pseudo-monthly urine: triethylamine (34_5 ml, 245.7 mmol) and ethyl chloroantimonate (2 〇.65 g, 245 mmol) The ear) was added to a mixture of 2-methyl-2-thiosulphonic acid g (22.8 g, 81 -9 mol) in methylene chloride (2 mL). After stirring overnight, the mixture was washed with water, brine, dried over sodium sulfate, filtered and evaporated in vacuo to a spurt oil, which was subjected to flash chromatography (10% ethyl acetate/hexane) to provide The title compound (16.68 g, 86.9% Y) was obtained as colorless oil. iHNMR (500 Mhz, CDC13) 5 1.3 (q, 6H), 2.41 (s, 3H), 4.22 (m, 4H). Example 25

N，N-二乙基脲醯胺基_2_曱基-2-硫假脲：異氰酸乙酯 (1.137毫升，14.37毫莫耳）接著逐滴6 N NaOH加到2-甲基-2- O:\90\90896-DOC -73- 1334416 硫假脲硫酸酯（2.0克，7.18毫莫耳）在水（3毫升）中的混合物 至穩定的pH 8。在pH 8 1個小時之後二相溶液以飽和礙酸氫 鈉水溶稀釋和萃取於乙酸乙酯（3x100毫升）中。合併有之機 層以鹽水洗滌和經過硫酸鈉乾燥，過濾然後在真空中濃縮 以提供刺鼻的油狀物之標題化合物（1.54克，92.7%)。 TLC(5 0%乙酸乙酯/二氯曱烷）和1H NMR提議物質為單和二 醯基硫假脲的混合物。1HNMR(500Mhz, CDC13) 5 1.18(m2,6H)， 2.31 及2·41 (2s，3H)，3.28(m,4H)。 實例26 &lt;1N,N-diethylureido-amino-2-yl-nonylthiourea: ethyl isocyanate (1.137 ml, 14.37 mmol) followed by dropwise addition of 6 N NaOH to 2-methyl- 2- O:\90\90896-DOC -73- 1334416 A mixture of sulphur pseudourea sulfate (2.0 g, 7.18 mmol) in water (3 ml) to a stable pH 8. After 1 hour at pH 8, the biphasic solution was diluted with saturated aqueous sodium sulphate and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with EtOAc (EtOAc m. The TLC (50% ethyl acetate / dichloromethane) and 1H NMR proposed material is a mixture of mono- and di-decylthiourea. 1H NMR (500Mhz, CDC13) 5 1.18 (m2, 6H), 2.31 and 2.41 (2s, 3H), 3.28 (m, 4H). Example 26 &lt;1

[5-(4-環丙基胺曱醯基-p比嗤_1_基）_7_鳴咬_2_基_ih-苯并 咪°坐-2·基]-胺基甲酸乙酯：Ra_Ni(2滴的水漿液，催化）加到 1-(3-胺基-4-硝基-5-嘧咬-2-基-苯基）-1Η-咪唾-4-羧酸環丙 基醯胺（65毫克’ 0.178毫莫耳）在MeOH( 10毫升）中的溶液及 所得懸浮液在45 psi之H2(Parr搖盡機）下放置2小時。然後過 濾所得混合物，濃縮，以3毫升的PH =3.5緩衝液稀釋（從1 μ HjO4與充足的NaOAc升高至pH到3.5製造），及在室溫下以 N，N-二乙基羧基-2-甲基-2-硫假脲（0.267毫升之N，N-二乙基 1334416 羧基-2-曱基-2-硫假脲在二崎烷中的1 μ溶液）處理。所得混 合物回流5小時產生不均懸浮液。反應冷卻到室溫，以水稀 釋和以充足的ΝΗ4〇Η升高pH〜6.0。然後過濾該等固體及以 水、2/1水/乙醇、EtOAc，然後己烷洗滌。所得固體懸浮在 Me〇H中止，加入2當量的曱烷磺酸，和在真空中濃縮以提 供灰白色固體的標題化合物（75，7〇%)。iH (dms()_d6, 5㈨ MHz): 9.28 (s, 1H); 9.08 (d, 1H); 8.8-7.4 (v. %s, 4H); 8.67 (s, 1H); 8.53 (s, 1H); 8.46 (d, 1H); 8.05 (d, 1H); 7.59 (dd, 1H); 4.33 (q, 2H); 2.88 (m, 1H); 2.35 (s，6H); 1.34 (t，3H); 0.76 (m，2H); 0.61 (m，2H)。 實例27 我們已藉由實質上與流程Mv中所述之方法相同的方 法，實例1至26，和藉由該技藝已知的方法製備式j之其他 化σ物這些化合物的定性數據概述在下表3中且包括 LC/MS(觀察）和NMR數據。 H NMR數據概述在下表3中，其中1h 在氘化 中於50G MHz獲％•，除非另有指示，且發現與結構—致。化 合物編號對應於該等列在表2中之化合物編號。[5-(4-Cyclopropylaminoindolyl-p~嗤_1_yl)_7_Bite bite_2_yl_ih-benzomidine~2-yl]-carbamic acid ethyl ester: Ra_Ni (2 drops of water slurry, catalyzed) to 1-(3-Amino-4-nitro-5-pyridin-2-yl-phenyl)-1Η-imidazole-4-carboxylic acid cyclopropyl A solution of the guanamine (65 mg '0.178 mmol) in MeOH (10 mL) and the resulting suspension was placed at &lt;RTIgt;&lt;/RTI&gt; The resulting mixture was then filtered, concentrated, diluted with 3 mL of pH = 3.5 buffer (manufactured from 1 μHjO4 with sufficient NaOAc to pH to 3.5), and N,N-diethylcarboxyl at room temperature. 2-Methyl-2-thiol-urea (0.267 mL of N,N-diethyl 1334416 carboxy-2-indolyl-2-thiopyreureate in 1 μ solution in dioxane). The resulting mixture was refluxed for 5 hours to give a heterogeneous suspension. The reaction was cooled to room temperature, diluted with water and raised to pH 6.0 with sufficient ent. The solids were then filtered and washed with water, 2/1 water/ethanol, EtOAc then hexane. The resulting solid was suspended in EtOAc (EtOAc) (EtOAc) iH (dms()_d6, 5(9) MHz): 9.28 (s, 1H); 9.08 (d, 1H); 8.8-7.4 (v. %s, 4H); 8.67 (s, 1H); 8.53 (s, 1H) 8.46 (d, 1H); 8.05 (d, 1H); 7.59 (dd, 1H); 4.33 (q, 2H); 2.88 (m, 1H); 2.35 (s, 6H); 1.34 (t, 3H); 0.76 (m, 2H); 0.61 (m, 2H). Example 27 We have prepared qualitative data for these compounds by essentially the same methods as those described in Scheme Mv, Examples 1 to 26, and by methods known in the art. 3 and include LC/MS (observation) and NMR data. The H NMR data is summarized in Table 3 below, where 1 h was obtained at 50 G MHz in deuteration, unless otherwise indicated, and found to be structurally related. The compound numbers correspond to the compound numbers listed in Table 2.

O:\90\90896.DOC 75· 1334416 表3.選擇之式I化合物的定性數據O:\90\90896.DOC 75· 1334416 Table 3. Qualitative data for the selected compound of formula I

化合物編號I- M-1 (obs) M+1 (obs) 'HNMR 16 347.2 349.2 1.1 (t, 3H) 3.2 (q52H) 6.8 (t,lH) 7.5 (m，lH)，7.7(s，lH)7.9(s，lH)8.1 (d，lH) 8.3 (s,lH) 8.6 (d,lH) 8.9 (s,lH)9.6 (slH) 10.3 (s,lH) 20 360.3 362.3 (CD3〇D): 8.89 (dd, 1H); 8.51 (dd, 1H); 8.42-8.29 (br. s, IH), 8.18 (ddd, 1H); 7.94-7.77 (br. s, 1H); 7.63 (br. s); 7.58 (br. s, 1H); 7.53 (dd, 1H); 3.32 (q? 2H); 2.21 (s, 3H);1.23 (t, 3H) 24 391.3 393.3 1.13(t, 3H), 1.3(t5 3H) 3.24 (q, 2H), 3.37(q，2H), 7.82(s，1H)，7.82(slH)， 7.96(t，lH)8.19(s，lH)， 8.56(s，lH)，8.62(d，lH), 8.82(d，lH),9.15(s，lH)，11.02(s，lH) 42 390.3 392.2 1.13 (t, 3H) 2.45 (s5 3H) 3.23 (q,2H) 3·46 (s，3H) 6.58 (m，4H)，7.78 (m，3H) 9.11 (s, 1H) 10.51 (s,lH) 12.18 (s,lH) 43 - - 1.15 (t，3H), 3.25 (m，2H)，3.35 (s，3H), 4.6 (s，2H), 7.4 (br s，1H)，7.55 (s, 1H), 7.8 (m，1H)，8.0 (d，1H)，8.05 (d，1H)， 8.6 (m51H), 8.7 (m, 1H), 9.2 (s, 1H), 10.4 (brs, 1H) 49 - - 1.3 (t, 3H), 4.3 (q, 2H), 6.65 (t, 1H), 7.75 (d, 1H), 7.85 (dd, 1H), 7.9 (s, 1H), 8.05 (d, 1H)S 8.5 (d5 1H)S 8.75 (dd? 1H), 9.1 (s, 1H0, 11.7 (brs, 1H), 50 377.2 379.1 1.23 (t, 3H), 2.89 (s, 3H), 3.36 (q, 2H), 7.93 (d, 1H), 8.16 (d3 1H), 8.26 (ds 1H), 8.33 (d51H), 8.86 (d, 1H); 8.97 (d; 1H), 9.30 (d, 1H) 51 - - 1.1 (t, 3H), 1.25 (t, 3H), 3.25(q, 2H), 3.37 (s, 3H)，4.05(q, 2H)，6.6 (m，4H)， 7.65 (s,lH), 7.9 (ms2H) 9.1 (br s,lH), 10.2(brs,lH), 11.8 (br s, 1H) 54 • - 0.5 (m，2H)，0.8 (m, 2H)，2.7 (m，1H)， 6.4 (br s, 1H), 6.7 (m, 1H), 7.75 (s, 1H), 7.8 (m, 1H), 7.85 (s, 1H), 8.05 (m, 1H), 8.5 (brs, 1H)S 8.7 (m, 1H), 9.05 (s, 1H)S 9.15 (s, 1H), 10.2 (brs, 1H) 55 - - 1.15 (t, 3H), 3.25 (m, 2H), 7.25 (m, 1H), 7.5 (br s, 1H), 7.7 (m, 1H)S 7.85 (s, 1H)S 8.3 (s, 1H), 8.4 (m, 1H), 8.7 (m, 2H), 8.85 (s, 1H), 9.1 (s, 1H)5 9.15 (dds 1H), 10.5 (brs, 1H), 57 377.1 379.2 9.08 (d, 1H); 8.48 (br. s, lh); 8.135(d5 1H); 7.95 (d, 1H); 7.88 (s, 1H); 7.25 (d, 1H); 6.75 (d, 1H); 6.64 (s, 1H);,6.62 (dd, 1H); 6.4-5.7 (br. s, 2H); 5.69 (q, 2H); 3.48 (s3 3H); 1.48 (t, 3H) 61 - - 1.13(t, 3H) 2.38(s, 3H) 3.24(q, 2H) 5.36(s, 2H) 6.71(m? 2H)S 6.83(s? 1H) 7.18(d, 2H) 7.28(tslH) 7.38(m,2H) 7.76(s,lH) 7.92(s52H)58.30(s,1H) 9.08(ss1H) 11.50(s51H) 62 404.3 406.3 12.15, 11.81 (s, 1H), 10.34,9.99 (s, 1H), 9.13, 8.99 (s, 1H), 7.99-7.81 (ms 3H), 7.68 (s, 1H), 7.30-6.59 (m, 4H), 5.09 (m. O:\90\90896.DOC -76· 1334416 化合物編號I- M-l (obs) M+l (obs) 'HNMR 1H), 3.23 (t, 2H), 1.33 9(d, 6H), 1.13 (t, 3H) 63 - - 1.15(t, 3H) 2.44(s, 3H) 3.25(qs 2H) 5.44(s, 2H) 6.70(m, 3H), 7.40(d,lH) 7.49(t,lH) 7.75(sslH) 7.85(m,lH) 7.97(s，2l·^ 8.12j；s，lH^8.60(d，lH) 9.09(s，lH) 11.21(s，lH) 64 - - 1.2 (t, 3H), 2.2 (m, 2H), 3.3 (m, 2H), 3.65 (m, 2H), 4.1 (t? 2H), 7.75 (s, 1H), 7.84 (s, 1H), 7.87 (s5 1H); 7.8 (m, 1H0, 8.5 (m, 1H), 8.65 (m, 1H), 9.0 (s, 1H) 65 423.1 425.1 (MeOH-d4 &amp; CDC13): 8.30-7.85 (m, 4H), 6.78(s，1H)，6.58 (s，1H)，3.60 (s，3H)， 3.37 (qs 2H), 2.80 (s, 3H), 1.25 (t, 3H) 67 - - 1.15 (t, 6H), 3.45 (q, 4H)S 6.7 (s, 1H), 7.7 (m5 2H), 7.9 (s, 1H), 8.1 (s5 1H), 8.4 (m, 1H), 8.7 (m, 1H), 9.1 (m, 2H), 10.6 (br s, 1H), 68 453.2 455.2 12.17, 11.81 (s，1H)，10.35, 9.99 (s，1H)， 9.13,9.00 (s, 1H), 8.52 (s, 1H), 7.99-7.69 (m, 5H), 7.32-7.27 (m, 2H), 6.93-6,59 (m, 4H), 5.23 (s, 2H), 3.22 (q, 2H)S 1.13 (t,3H) 69 407.3 409.2 (MeOH-d4, HC1 salt)): 8.62 (s, 1H)S 7.96-7.93 (m，2H)，7.59 (s, 1H)，6.67 (s, 1H), 5.81 (s, 1H)S 3.45, 3.39 (s, 3H)S 3.36 (q, 2H), 3.28, 3.20 (s, 3H), 1.23 (t, 3H) 70 - - 1.15 (t, 3H), 1.35 (t, 3H), 3.25 (q, 2H), 4.3 (q5 2H), 7.1 (br s, 1H), 7.85 (s, 1H), 8.05 (m, 1H), 8.2 (s, 1H), 8.3 (s, 1H), 8.8 (ms 1H), 8.85 (d, 1H), 9.25 (s, 1H0, 9.65 (s, 1H), 10.7 (brs, 1H), 71 416.2 418.2 O.S4(m, 2H) 1.14(ms 5H) 2.55(s, 3H) 2.91(m,lH) 3.26(qs2H),6.59(s,lH) 6.65(s,lH) 6.69 (sslH) 7.65(s,lH) 7.81(m，lH) 7.97 (s,1H)，8.07(s，1H) 9.07(s,lH) 11.59(s,lH) 72 - - 1.1 (t，3H)，3.2 (q，2H)，7.1 (br s，1H)， 7.8 (s5 1H), 8Ό (m, 1H), 8.2 (s, 1H)S 8.25 (s，1H)，8.7 (m，1H)，8.8 (m，1H)，9.2 (s， 1H), 9.6 (s, 1H), 10.7 (brs, 1H), 73 448.2 450.2 (CD3OD): 1.18-1.26 (m，9H)，3.27 (s， 3H)，3.36 (q，2H)，4.21 (s，2H)，6.65-6.68 (m, 1H)，6.90-6.94 (m，1H)，6.98-7.01 (m，1H)，7.78-7.84 (m，2H)，7.93-7.96 (m，1H)，8.09-8.11 (m，1H)，8.74-8.76 (m, 1H) 74 434.3 436.3 (CD3OD): 1.21-1.27 (m, 9H), 3.36 (q, 2H), 4.17 (ss 2H), 6.65-6.68 (m, 1H), 6.95-6.99 (m, 1H), 7.00-7.03 (m, 1H)， 7.79-7.82 (m, 1H), 7.89 (d, 1H), 7.94-7.96 (m，1H)，8.09-8.11 (m，1H)， 8.73-8.76 fm, 1H) 75 - - 1.1 (ts 3H), 3.0 (br s, 3H), 3.25 (m, 5H), 7.0 (br s, 1H), 7.75 (m, 2H), 8.05 (ss 1H), 8.15 (s5 1H)S 8.45 (m, 1H), 8.7 (m, 1H), 9.1 (s5 1H), 9.4 (s, 1H), 10.4 (br s, 1H),Compound No. I- M-1 (obs) M+1 (obs) 'HNMR 16 347.2 349.2 1.1 (t, 3H) 3.2 (q52H) 6.8 (t,lH) 7.5 (m,lH), 7.7(s,lH) 7.9(s,lH)8.1 (d,lH) 8.3 (s,lH) 8.6 (d,lH) 8.9 (s,lH)9.6 (slH) 10.3 (s,lH) 20 360.3 362.3 (CD3〇D): 8.89 (dd, 1H); 8.51 (dd, 1H); 8.42-8.29 (br. s, IH), 8.18 (ddd, 1H); 7.94-7.77 (br. s, 1H); 7.63 (br. s); 7.58 (br. s, 1H); 7.53 (dd, 1H); 3.32 (q? 2H); 2.21 (s, 3H); 1.23 (t, 3H) 24 391.3 393.3 1.13(t, 3H), 1.3(t5 3H) 3.24 (q, 2H), 3.37 (q, 2H), 7.82 (s, 1H), 7.82 (slH), 7.96 (t, lH) 8.19 (s, lH), 8.56 (s, lH), 8.62 (d, lH), 8.82(d,lH),9.15(s,lH),11.02(s,lH) 42 390.3 392.2 1.13 (t, 3H) 2.45 (s5 3H) 3.23 (q,2H) 3·46 (s,3H 6.58 (m,4H), 7.78 (m,3H) 9.11 (s, 1H) 10.51 (s,lH) 12.18 (s,lH) 43 - - 1.15 (t,3H), 3.25 (m,2H),3.35 (s, 3H), 4.6 (s, 2H), 7.4 (br s, 1H), 7.55 (s, 1H), 7.8 (m, 1H), 8.0 (d, 1H), 8.05 (d, 1H), 8.6 (m51H), 8.7 (m, 1H), 9.2 (s, 1H), 10.4 (brs, 1H) 49 - - 1.3 (t, 3H), 4.3 (q, 2H), 6.65 (t, 1H), 7.75 ( d, 1H), 7 .85 (dd, 1H), 7.9 (s, 1H), 8.05 (d, 1H)S 8.5 (d5 1H)S 8.75 (dd? 1H), 9.1 (s, 1H0, 11.7 (brs, 1H), 50 377.2 379.1 1.23 (t, 3H), 2.89 (s, 3H), 3.36 (q, 2H), 7.93 (d, 1H), 8.16 (d3 1H), 8.26 (ds 1H), 8.33 (d51H), 8.86 (d, 1H); 8.97 (d; 1H), 9.30 (d, 1H) 51 - - 1.1 (t, 3H), 1.25 (t, 3H), 3.25(q, 2H), 3.37 (s, 3H), 4.05 (q , 2H), 6.6 (m, 4H), 7.65 (s, lH), 7.9 (ms2H) 9.1 (br s, lH), 10.2 (brs, lH), 11.8 (br s, 1H) 54 • - 0.5 (m , 2H), 0.8 (m, 2H), 2.7 (m, 1H), 6.4 (br s, 1H), 6.7 (m, 1H), 7.75 (s, 1H), 7.8 (m, 1H), 7.85 (s , 1H), 8.05 (m, 1H), 8.5 (brs, 1H)S 8.7 (m, 1H), 9.05 (s, 1H)S 9.15 (s, 1H), 10.2 (brs, 1H) 55 - - 1.15 ( t, 3H), 3.25 (m, 2H), 7.25 (m, 1H), 7.5 (br s, 1H), 7.7 (m, 1H)S 7.85 (s, 1H)S 8.3 (s, 1H), 8.4 ( m, 1H), 8.7 (m, 2H), 8.85 (s, 1H), 9.1 (s, 1H)5 9.15 (dds 1H), 10.5 (brs, 1H), 57 377.1 379.2 9.08 (d, 1H); 8.48 (br. s, lh); 8.135 (d5 1H); 7.95 (d, 1H); 7.88 (s, 1H); 7.25 (d, 1H); 6.75 (d, 1H); 6.64 (s, 1H); 6.62 (dd, 1H); 6.4-5.7 (br. s, 2H); 5.69 (q, 2H); 3.48 (s3 3H); 1.48 (t, 3H) 61 - - 1.13(t, 3H) 2.38(s, 3H) 3.24(q, 2H) 5.36(s, 2H) 6.71(m? 2H)S 6.83(s? 1H 7.18(d, 2H) 7.28(tslH) 7.38(m,2H) 7.76(s,lH) 7.92(s52H)58.30(s,1H) 9.08(ss1H) 11.50(s51H) 62 404.3 406.3 12.15, 11.81 (s, 1H), 10.34,9.99 (s, 1H), 9.13, 8.99 (s, 1H), 7.99-7.81 (ms 3H), 7.68 (s, 1H), 7.30-6.59 (m, 4H), 5.09 (m. O :\90\90896.DOC -76· 1334416 Compound No. I- Ml (obs) M+l (obs) 'HNMR 1H), 3.23 (t, 2H), 1.33 9(d, 6H), 1.13 (t, 3H 63 - - 1.15(t, 3H) 2.44(s, 3H) 3.25(qs 2H) 5.44(s, 2H) 6.70(m, 3H), 7.40(d,lH) 7.49(t,lH) 7.75(sslH) 7.85(m,lH) 7.97(s,2l·^ 8.12j;s,lH^8.60(d,lH) 9.09(s,lH) 11.21(s,lH) 64 - - 1.2 (t, 3H), 2.2 ( m, 2H), 3.3 (m, 2H), 3.65 (m, 2H), 4.1 (t? 2H), 7.75 (s, 1H), 7.84 (s, 1H), 7.87 (s5 1H); 7.8 (m, 1H0, 8.5 (m, 1H), 8.65 (m, 1H), 9.0 (s, 1H) 65 423.1 425.1 (MeOH-d4 &amp; CDC13): 8.30-7.85 (m, 4H), 6.78(s,1H), 6.58 (s,1H), 3.60 (s,3H), 3.37 (qs 2H), 2.80 (s, 3H), 1.25 (t, 3H) 67 - - 1.15 (t, 6H), 3.45 (q, 4H)S 6.7 (s, 1H), 7.7 (m5 2H), 7.9 (s, 1H), 8.1 (s5 1H), 8.4 (m, 1H), 8.7 (m, 1H), 9.1 (m, 2H), 10.6 (br s, 1H) , 68 453.2 455.2 12.17, 11.81 (s, 1H), 10.35, 9.99 (s, 1H), 9.13, 9.00 (s, 1H), 8.52 (s, 1H), 7.99-7.69 (m, 5H), 7.32-7.27 (m, 2H), 6.93-6,59 (m, 4H), 5.23 (s, 2H), 3.22 (q, 2H)S 1.13 (t,3H) 69 407.3 409.2 (MeOH-d4, HC1 salt)): 8.62 (s, 1H)S 7.96-7.93 (m, 2H), 7.59 (s, 1H), 6.67 (s, 1H), 5.81 (s, 1H)S 3.45, 3.39 (s, 3H)S 3.36 (q, 2H), 3.28, 3.20 (s, 3H), 1.23 (t, 3H) 70 - - 1.15 (t, 3H), 1.35 (t, 3H), 3.25 (q, 2H), 4.3 (q5 2H), 7.1 ( Br s, 1H), 7.85 (s, 1H), 8.05 (m, 1H), 8.2 (s, 1H), 8.3 (s, 1H), 8.8 (ms 1H), 8.85 (d, 1H), 9.25 (s , 1H0, 9.65 (s, 1H), 10.7 (brs, 1H), 71 416.2 418.2 O.S4(m, 2H) 1.14(ms 5H) 2.55(s, 3H) 2.91(m,lH) 3.26(qs2H), 6.59(s,lH) 6.65(s,lH) 6.69 (sslH) 7.65(s,lH) 7.81(m,lH) 7.97 (s,1H),8.07(s,1H) 9.07(s,lH) 11.59(s ,lH) 72 - - 1.1 (t,3H),3.2 (q,2H),7.1 (br s,1H), 7.8 (s5 1H), 8Ό (m, 1H), 8.2 (s, 1H)S 8.25 ( s,1H),8.7 (m,1H),8.8 (m,1 H), 9.2 (s, 1H), 9.6 (s, 1H), 10.7 (brs, 1H), 73 448.2 450.2 (CD3OD): 1.18-1.26 (m, 9H), 3.27 (s, 3H), 3.36 (q , 2H), 4.21 (s, 2H), 6.65-6.68 (m, 1H), 6.90-6.94 (m, 1H), 6.98-7.01 (m, 1H), 7.78-7.84 (m, 2H), 7.93-7.96 (m,1H), 8.09-8.11 (m,1H),8.74-8.76 (m, 1H) 74 434.3 436.3 (CD3OD): 1.21-1.27 (m, 9H), 3.36 (q, 2H), 4.17 (ss 2H) ), 6.65-6.68 (m, 1H), 6.95-6.99 (m, 1H), 7.00-7.03 (m, 1H), 7.79-7.82 (m, 1H), 7.89 (d, 1H), 7.94-7.96 (m ,1H),8.09-8.11 (m,1H), 8.73-8.76 fm, 1H) 75 - - 1.1 (ts 3H), 3.0 (br s, 3H), 3.25 (m, 5H), 7.0 (br s, 1H ), 7.75 (m, 2H), 8.05 (ss 1H), 8.15 (s5 1H)S 8.45 (m, 1H), 8.7 (m, 1H), 9.1 (s5 1H), 9.4 (s, 1H), 10.4 ( Br s, 1H),

O:\90\90896.DOC -77- 1334416 化合物編號I- M-l (obs) M+l (obs) 'h nmr 77 448.3 450.2 (CD3OD): d 1.24 (t, 3H), 1.27 (d, 3H), 1.47 (d，3H), 3.36 (q，2H)，3·37 (s，3H)， 3.58-3.67 (m，1H)，5.21-528 (m，1H)， 6.68-6.71 (m, 1H), 7.80 (d, 1H), 7.85 (s, 1H), 7.95-7.99 (m, 2H), 8.27 (s, 1H), 8.38 (d，1H), 8,78-8.82 (m，1H). 78 448.3 450.3 (CD3OD): d 1.24 (t，3H)，1.31 (d，3H)， 1.51 (d, 3H), 3.38 (q, 2H), 3.42 (s, 3H), 3.66-3,73 (m, 1H), 5.44-5.51 (m, 1H)S 6.68-6.71 (ms 1H), 7.94 (ds 1H), 7.96-7.98 (m; 1H), 8.03 (s, 1H), 8.07 (s, 1H)S 8.32 (s, 1H), 8.43 (d, 1H), 8.81-8.86 (m, 1H). 79 434.3 436.2 (CD3OD): d 1.24 (t3 3H), 1.32 (d, 3H), 1.50 (d, 3H), 3.37 (q5 2H), 3.93-4.02 (m, 1H), 5.14-5.22 (m, 1H), 6.67-6.71 (m, 1H), 7.90 (d, 1H), 7.95-7.98 (m, 1H), 8.02 (s, 1H), 8.04 (s5 1H)5 8.32 (s5 1H)? 8.41 (d, 1H)S 8.81-8.85 (m, 1H). 82 428.2 430.1 9.0 (m, 1H), 8.6 (d, 1H), 8.4 (m, 1H), 8.1-8.2 (m, 2H), 8.0 (m, 1H), 7.8 (m, 1H), 7.5 (m, 2H), 6.6 (s, 1H), 4.8 (s, 1H), 2.55 (s，3H)，3.25 (m, 2H)，2.1 (s，3H), 1.1 (t, 3H) 83 417.1 419.1 11.01 (br. s, 1H); 9.10 (d5 1H); 8.37,(s, 1H); 8.19 (s, 1H); 7.97 (s, 1H); 7.78 (br. s, 1H); 7.58 (m, 1H); 7.08,( s, 1H); 6.68 (m, 1H); 3.88 (dd, 2H); 3.22 (dq, 2H); 2.99 (dd, 2H); ,1.91 (ddd5 2H); 1.85 (ddd,2H); 1.11 (t, 3H). 84 377,2 379.2 (MeOD-d3): 8.72 (br s, 1H), 8.58 (s5 1H), 8.40 (s，1H), 8.19 (s，1H)5 7.95 (s，1H)， 7.14 (s，1H)，6.68 (s，1H)，3.60 (s，3H)， 3.21 (q, 2H), 1.24 (t, 3H). 85 430.2 432.2 (MeOD-d3i salt): 8.64 (d, 1H), 8.14 (s, 1H)，8.00 (s，1H)，7.97 (d，1H)，7.64 (s， 1H)，6.66 (dd，1H)，6.51 (s，1H)，3.89 (s， 3H)，3.48 (s，3H)，3.37 (q，2H)，1.24 (t， 3H) 87 360.1 362.1 MeOD-d3, 1.24 (ts 3H)S 2.42 (s,3H), 3.38 (q，2H)，6.87 (s，lH)，7.94 (s，lH),8·15 (m，2H)，8.85 (d，lH)，8.98 (d，lH)，9.30 (s，lH) 88 388 390 9.27 (s，2H). 9.20 (S，1H)，8,27(s，1H). 8.10 (m, 1H), 7,94(s, H), 7.92(d, 1H), 6.95(d, 1H), 4.10(s, 3H), 3.25(m, 2H), 1.11 (t,3H) 89 386.9 389.2 (CD3OD) 8.92-6.96 (m, 9ArH), 3.99 (s, 3H), 3.36 (q, 2H), 1.24 (t, 3H) 90 457.1 459.2 -O:\90\90896.DOC -77- 1334416 Compound No. I- Ml (obs) M+l (obs) 'h nmr 77 448.3 450.2 (CD3OD): d 1.24 (t, 3H), 1.27 (d, 3H) , 1.47 (d,3H), 3.36 (q,2H),3·37 (s,3H), 3.58-3.67 (m,1H),5.21-528 (m,1H), 6.68-6.71 (m, 1H) , 7.80 (d, 1H), 7.85 (s, 1H), 7.95-7.99 (m, 2H), 8.27 (s, 1H), 8.38 (d, 1H), 8,78-8.82 (m,1H). 78 448.3 450.3 (CD3OD): d 1.24 (t,3H), 1.31 (d,3H), 1.51 (d, 3H), 3.38 (q, 2H), 3.42 (s, 3H), 3.66-3,73 (m, 1H), 5.44-5.51 (m, 1H)S 6.68-6.71 (ms 1H), 7.94 (ds 1H), 7.96-7.98 (m; 1H), 8.03 (s, 1H), 8.07 (s, 1H)S 8.32 (s, 1H), 8.43 (d, 1H), 8.81-8.86 (m, 1H). 79 434.3 436.2 (CD3OD): d 1.24 (t3 3H), 1.32 (d, 3H), 1.50 (d, 3H), 3.37 (q5 2H), 3.93-4.02 (m, 1H), 5.14-5.22 (m, 1H), 6.67-6.71 (m, 1H), 7.90 (d, 1H), 7.95-7.98 (m, 1H), 8.02 (s, 1H), 8.04 (s5 1H)5 8.32 (s5 1H)? 8.41 (d, 1H)S 8.81-8.85 (m, 1H). 82 428.2 430.1 9.0 (m, 1H), 8.6 (d, 1H) , 8.4 (m, 1H), 8.1-8.2 (m, 2H), 8.0 (m, 1H), 7.8 (m, 1H), 7.5 (m, 2H), 6.6 (s, 1H), 4.8 (s, 1H) ), 2.55 (s, 3H) , 3.25 (m, 2H), 2.1 (s, 3H), 1.1 (t, 3H) 83 417.1 419.1 11.01 (br. s, 1H); 9.10 (d5 1H); 8.37, (s, 1H); 8.19 (s , 1H); 7.97 (s, 1H); 7.78 (br. s, 1H); 7.58 (m, 1H); 7.08, (s, 1H); 6.68 (m, 1H); 3.88 (dd, 2H); (dq, 2H); 2.99 (dd, 2H); , 1.91 (ddd5 2H); 1.85 (ddd, 2H); 1.11 (t, 3H). 84 377,2 379.2 (MeOD-d3): 8.72 (br s, 1H), 8.58 (s5 1H), 8.40 (s,1H), 8.19 (s,1H)5 7.95 (s,1H), 7.14 (s,1H),6.68 (s,1H), 3.60 (s,3H) , 3.21 (q, 2H), 1.24 (t, 3H). 85 430.2 432.2 (MeOD-d3i salt): 8.64 (d, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.97 (d, 1H), 7.64 (s, 1H), 6.66 (dd, 1H), 6.51 (s, 1H), 3.89 (s, 3H), 3.48 (s, 3H), 3.37 (q, 2H), 1.24 (t, 3H) 87 360.1 362.1 MeOD-d3, 1.24 (ts 3H)S 2.42 (s,3H), 3.38 (q,2H), 6.87 (s,lH),7.94 (s,lH),8·15 (m,2H) , 8.85 (d, lH), 8.98 (d, lH), 9.30 (s, lH) 88 388 390 9.27 (s, 2H). 9.20 (S, 1H), 8, 27 (s, 1H). 8.10 (m , 1H), 7,94(s, H), 7.92(d, 1H), 6.95(d, 1H), 4.10(s, 3H), 3.25(m, 2H), 1.11 (t,3H) 89 386.9 389.2 (CD3OD) 8.92-6.96 (m, 9ArH), 3.99 (s, 3H), 3.36 (q, 2H), 1.24 (t, 3H) 90 457.1 459.2 -

O:\90\90896.DOC 78- 1334416 化合物编號I- M-l (obs) M+l (obs) *HNMR 91 429.2 431.2 (CD30D): 8.97 (s3 1H); 8.89 (d, 1H); 8.49 (d, 1H); 8.37 (m, 2H); 8.22 (ddd, 1H); 7.93 (d, 1H); 7.64 (dd, 1H); 3.38 (q, 2H);2.91 (m, 1H); 1.25 (t, H): 0.88 (m, 2H); 0.67 (m, 2H). 92 360.13 362.19 1.15 (t, 3H), 3.25 (m, 2H), 3.9 (s, 3H), 7.15 (m，1H), 7.65 (m，1H)，7.8 (s5 1H), 8.0 (s, 1H), 8.2 (m, 1H), 8.3 (m, 1H)S 8.65 (m，1H)，9_0 (m，2H)，10.3 (br s， 1H) 93 371 373 1.12(t，3H)，3.25(m，2H)，4.2(bs,2H)， 7.0.2-7.25(m，lH)，7.5(m，1H)， 7.81(m，lH)，8.08(t，lH)，8.22(m，lH)， 8.61-8.48(m,2H), 8.4(d,lH),8.46(s5lH). 94 430 432 0.92(ά,6Η), 1.12(m,3H), 2.23(m.lH)，2.83(d，2H)，3.35(m，2H)， 7.5(m，lH)，7.61(bs，lH)，7.89 (s，lH)，8.1(m，lH)，8.4(s,lH)， 8.58(m，lH)，8.78(bs，lH)，8.3(d，lH). 95 431.03 433.2 (CD3OD) 1.2 (7, 3H), 3.3 (q, 2H), 3.8 (m，2H)，4.6 (m，2H)，7.4 (m，1H)，7.8 (m, 1H), 8.0 (s, 1H)5 8.3 (m, 2H); 8.5 (m, lH)，8.7(m,2H)，9.1(s，lH) 96 507.2 509.2 (CD3OD): 8.9(d, 1H)? 8.55(d, 1H), 8.4(s，1H)，8.3(m，lH)，8.0(s，lH)，7.7(m， 1H), 7.3(t, 1H), 7.0(s, 2H), 6.85(d, 1H), 6.7 (d, 2H)s5.5(s, 2H), 3.7(s, 3H)? 3.3(q, 2H)?2.5(s, 3H), 1.25 (t, 3H) 97 401 403 9.1 (s, 1H), 8.6 (d, 2H)S 8.3 (m, 1H)? 8.1 (s, 1H)5 7.9 (s, 1H)S 7.8 (s5 1H) 7.5 (m5 1H), 7.0 (dslH), 4.3 (m? 2H), 3.3 (m, 2H), 1.4 (t, 3H)S 1.1 (t, 3H). 98 497.03 499.18 ,U6(t，3H)3.25(q，2H)4.44(d，2H) 7.17(t,2H) 7.38(t,2H)7.53(t,lH) 7.79(mslH) 7.87(s,lH) 8.10(t,lH) 8.32(s，lH)8.51(s，lH) 8.57(d，lH) 8.77(s,lH)8.82(d,lH) 8.94(t,lH)11.10(br sJH) 99 432 434 - O:\90\90896.DOC -79- 1334416 化合物編號I- M-l (obs) M十 1 (obs) *HNMR 100 418.25 420.15 1.1 (t, 3H), 3.2 (m5 2H), 3.95 (s, 3H), 4.1 (s，2H)，7.2 (br s，1H)，7,25 (brs，1H)，7.9 (ss 1H), 8.2 (m? 1H), 8.25 (s, 1H), 8.7 (d, 1H), 9.05 (s5 2H)? 10.4 (br s, 1H) 101 431 433 8.65 (d, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 7.98 (d，1H)，7.78 (d，1H)，7.38 (m，1H)， 6.93 (s5 1H), 6.89 (dd, 1H),4.51 (q, 2H)5 3.63 (s，3H)，3.35 (q，2H)，1.55 (t，3H)， 1.22 (t, 3H) 102 375 377 8.86(d，1H)，8.69(m，1H)，8.52(d，1H)， 8.16(m，2H)，7.79(m，2H)，7.56(m，1H)， 7.50(m, 1H), 3.55(m? 2H)1.23S (t, 3H) 103 430 432.1 8.87 (br. s，1H); 8.81 (d，1H); 8.66(br. s·， 1H); 8.49 (s，1H); 8.39 (br. s·，1H); 8.25 (d, 1H); 8.09 (ddd, 1H); 7.87 (d, 1H); 7.52 (dd, 1H); 5.3 (very br. s, 5 H); 4.29 (q, 2H); 2.85(iti, 1H); 1.31 (t, 3H); 0.72 (m，2H); 0.63 (m, 104 417.19 419.14 i.l (t，3H)，3.2 (q，2H), 3·45 (s，3H)，4.1 (s，3H)，6.7 (dd，1H)，6.85 (d，1H)，7.15 (br s，1H)，7.35 (br s，1H)，7.8 (d，1H)， 7.95 (s，1H)，8.2 (s，1H)，8.4 (br s，1H)， 8.7 (d, 1H)，10.5 (brs，1H) 105 406 408 8.97 (br. s, 2H); 8.60 (d, 1H); 7.99 (br. s., 1H); 7.96 (m, 1H); 7.81 (br. s., 1H); 7.57 (m, 1H); 3.98 (s, 3H); 3.25 (m, 2H); 1.11 (t, 3H). 106 508.2 510.2 1·1 (t，3H)，2.4 (s，3H)，3.2 (q, 2H)，4_1 (s3 3H), 5.4 (s, 2H), 6.65 (s5 1H), 6.75 (s, 1H), 7.15 (br s, 1H)S 7.3 (m, 2H), 7.35 (m, 1H), 7.8 (m, 1H), 7.95 (s, 1H), 8.25 (s5 1H), 8.35 (br s5 1H)5 8.5 (ms 1H), 8.75 (m, 1H), 10.5 (brs, 1H) 107 495.2 497.2 8.8(m3 1H), 8.2(ms 1H), 7.9(s, 1H), 7.8(m，1H)，7.4(m，2H)，7,35(d，2H)， 7.25(d，2H)，6.7-6.8(m，2H)，5.3(2, 2H)， 4.0 (m, lH),3.4(q? 2H), 2.4(ss 3H), Ll(t, 3H) 108 417 419 9.12 (br. s, 1H); 8.60 (d, 1H); 8.39 (m, 1H); 8.36 (s, 1H); 8.25 ( s, 1H); 7.89 (s, 1H); 7.70 (dd, 1H); 7.41 (m, 1 H); 4.13 (s, 3H); 3.98 (s, 3H); 3.26 (m, 2H); 1.15 (t, 3H). O:\9O\90896.DOC -80- 1334416 化合物编號I- M-l (obs) M+l (obs) ^NMR 109 358.3 360.1 (CD30D) 9.61 (d, 1H), 9.22 (d? 1H), 8.83-8.79 (m5 3H)? 8.65 (d, 1H)S S.47 (d, 1H), 8.02 (dd, 1H)S 8.00 (s, 1H), 3.37 (q5 2H)S 1.24 (t, 3H) 110 388.3 390.2 (CDCI3) 14.05 (br s, 1H)S 12.85 (br s, 1H), 8.37 (t, 1H), 7.97 (d, 1H), 7.88 (ds 1H), 7.79-7.74 (m, 2H), 7.63 (dd, 1H), 7.46 (d, 1H), 6.62 (dd, 1H), 5.75 (br s, 1H), 3.45-3.40 (m, 2H), 1.27 (t, 3H) 111 492.3 494.1 10.3(s，lH)，8.9(d，lH); 8.6(m,lH), 8.5(d，lH)，8.2(s，lH)，8.05(t，lH)， 7.8-7.9(m? 2H), 7.5(m,2H), 7.4(d,lH), 7.3(m,lH)s6.7(s,lH), 6.6(s,lH), 3.3(q,2H)3 1.9(d,3H), l.l-1.2(t,3H). 112 475.2 477.2 10.62 (s, 1H); 8.74 (d, 1H); 8.65 (s, 1H); 8.40 (s, 1H); 8.28 (s, 1H); 8.23 (s, 1H); 7.87 (s, 1H); 7.43 (s, 1H);7.32 (ms 2H); 5.52-4.41 (br. s, 3H); 4.10 (s, 3H); 3.24 (dt, 2H); 1.41 (s, 9H); 1.13 (t, 3H). 113 494.2 496.2 (CD3OD) 9.06 (s, 1H); 8.93 (d, 1H); 8.71 (d, 1H); 8.50(m, 2H); 8.39 (s, 1H); 8.00 (s, 1H); 7.87 (dd, 1H); 7.42 (d5 2H); 7.35 (dds 2H); 7.25 (dd, 1H); 5.27 (q, 1H); 4.41 (q, 2H); 1.62 (d, 3H); 1.42 (t, 3H) 114 370.2 372.2 12.09 &amp; 12.74 (s, 1H), 10.25 &amp; 9.94 (s, 1H), 9.12 &amp; 8.94 (s, 1H), 8.35-6.58 (m, 9H)，3.24 (m，2H)，1.13 (t，3H) 115 442.1 444.3 (CD3OD) 8.65 (d，1H)，7.94 (s, 1H)，7.91 (d，1H)，7.72 (d，2H), 7.66 (s，1H)，7.40 (d, 2H), 6.63 (dd, 1H),4.52 (s, 2H)S 3.40 (t, 2H), 3.35 (q, 2H), 2.47 (t, 2H), 2.09-2.03 (m, 2H), 1.24 (t, 3H) 116 382 384 - 117 415 417 9.17 (br. s7 1H); 9.0 (m, 1H); 8.98 (d, 1H); 8.72 (d, 1H); 8.55 (m, 1H); 8.38 (s, 1H); 7.94 (s, 1H); 7.86 (d, 1H); 7.79 (m, 1H); 3.97 (s, 3H); 3.27 (m, 2H); 1.15 (t, 3H). 118 401 403 - 119 403.3 405.2 (CD3OD): 8.78 (s, 1H), 8.67 (d, 1H), O:\90\90896.DOC -81 · 1334416 化合物編號I- M-l (obs) M+l (obs) 'HNMR 8.37 (d，1H)，8.24 (d, 1H)，8.22 (s，1H)， 8.04 (d，1H)，7.91 (s，1H)，7.67(dd，1H)， 7.40 (dd，1H)，4.22 (s，3H)，3.34 (q，2H)， 1.23 (t, 3H) 120 434.32 436.23 1·1 (t，3H)，2.8 (s，6H)，3.2 (m，2H)，3.4 (s，3H)，4.6 (s，2H)，6.6 (d，1H)，6.8 (s， 1H)，7.2 (br s5 1H)，7.6 (s，1H)，7.8 (d， 1H), 7.9 (s, 1H), 7.95 (s, 1H), 10.0 (br s, lH)，10.2(brs，lH) 121 414 416 (CD3OD): 9.40 (br. s, 1H); 9.07(d, 1H); 8.98 (d, 1H); 8.91 (d, 1H); 8.80 (s, 1H);8.60 (s; 1H); 8.24 (dd, 1H); 8.11 (d, 1H); 7.84 (dd, 1H); 3.35 (m, 2H); 3.01 (s，3H); 1.25 (t，3H). 122 415 417 - 123 435.28 43726 1.3 (t, 3H)? 2.8 (s, 6H), 3.5 (s, 3H), 4.2 (q, 2H), 4.6 (s, 2H), 6.6 (dd, 1H), 6.7 (s, 1H), 7.7 (s, 1H), 7.8 (d, 1H), 8.0 (m, 2H), 10.1 (brs, 1H), 11.7 (brs, 1H) 124 431.2 433.2 9.28 (s, 1H); 9.08 (d, 1H); 8.8-7A (v. broad s, 4H);8.67 (s5 1H); 8.53 (s, 1H); 8.46 (d, 1H); 8.05 (d, 1H); 7.59 (dd, 1H); 4.33 (q, 2H); 2.88 (m, 1H); 2.35 (s, 6H); 1.34 (t, 3H); 0.76 (m, 2H); 0.61 (ms 2H). 125 447.4 - 9.10 (s, 1H); 8.60 (d, 1H); 8.47 (m, 2H); 7.95 (s5 1H); 7.83 (s, 1H); 7.12 (d, 1H); 5.2-3.6 (br. m, 7H); 2.86 (M, 1H); 1.30 (t, 3H); 0.75 (m, 2H); 0.64 (m, 2H) 126 439.2 441.2 (CDCI3) 13.89 (br s, 1H), 12.89 (br s, 1H), 8.28 (d, 1H)5 8.25 (d, 1H), 7.96 (d, 1H)，7.74(s，1H), 7.69-7.43 (m，6H)， 7.40 (ss 1H), 6.64 (dd, 1H), 6.11 (br s5 1H)，3.46-3.40 (m，2H), 1.27 (t，3H) 127 418.2 420.2 (CD3OD) 9.72 (d, 1H)S 8.87 (d, 1H), 8.82 (d, 1H), 8.11 (d, 1H), 8.09 (d, 1H), 7.85 (d，1H)，7.39 (d，1H)，7.36 (d，1H)， 4.43(q，2H)，3.35 (q，2H)，1·44 (t，3H)， 1.24 (t, 3H) 128 449.8 452.1 (CD3OD) 9.21 (d, 1H), 8.83(ddd, 1H)S 8.81 (dd, 1H)S 8.68 (d, 1H), 8.26 (d5 1H), 8.18 (d, 1H), 8.07 (dd, 1H), 8.05 (d, 1H), 7.50 (dd，1H)，3.36 (q，2H)，3.34 (s，3H)， O:\9O\90896.DOC -82- 1334416 化合物編號I- M-l (obs) M+l (obs) 'HNMR 1.23 (t, 3H) 129 - - 9.31 (s, 1H); 9.08 (d, 2H); 8.63 (s, 1H); 8.43 (d, 1H); 8.02 (d, 1H); 7.89 (s5 1H); 7.57 (t5 1H); 8.8-6.6 (very br. s, 4H); 4.31 (q, 2H); 2.32 (s, 6H); 1.42 (s, 9H); 1.33(t, 3H). 130 495.4 497.2 9.07 (d, 2H); 8.73 (d, 1H); 8.56 (s, 1H); 8.44 (d, 1H); 8.03 (d, 1H); 7.57 (t, 3H); 7.44 (d, 2H); 7.36 (dd, 2H); 7.26 (dd, 1H); 6.95-5.90 (very broad s., 5H); 5.18 (dt, 1H); 4.32 (q5 2H); 2.32 (s5 6H); 1.53 (d5 3H);1.33(t, 3H). 131 432 434 (CD3OD) 1.08(d，6H), 1.43(t，3H)， 2,33(m，lH)，2.91(d，2H)，4.45(q，2H)， 7.53(t，lH)，8.08(s，lH)， 8.79(s，lH)&lt;8.94(s，lH)，9.05(d，2H), 9.5(s，lH). 132 514.23 516.23 8.84 (d, 1H), 8.81-8.83 (m; 1H), 8.35 (s5 1H)，8.06 (dd，1H)，7.90 (dd，1H)，7.80 (d, 1H), 6.80 (br s5 1H), 6.70 (d, 1H), 4.30 (q, 2H), 3.42-3.54 (m, 4H), 3.48 (s, 3H)，3.12-3.17 (m，4H)，2.81 (d, 3H)， 132 (t, 3H) ppm 133 501.33 503.26 - 134 521.6 523.2 (CD3OD) 8.82 (s，lH)，m 8.46 (d，1H)， 8.30 (s, 1H), 8.13 (dd, 1H), 7.90 (s, 1H), 7.55 (dd，1H)，7.28 (dd，1H)，6.86-6.77 (m，4H)，6.74 (s，1H)，3.77 (s，3H)，3.36 (q, 2H), 2.41 (br s, 3H), 1.97 (d, 3H), 1.24 (t, 3H) 135 470.3 472.5 (CD3OD) 8.85 (br s, 1H), 8.45 (d, 1H), 8.34 (dd，1H), 8/26 (dd，1H)，8.13 (ddds 1H), 7.96 (dd, 1H), 7.56 (dd, 1H), 7.43 (dds 1H), 7.29 &amp; 7.20 (ss 1H), 5.49 (m, 1H)，3.66-3.25 (m，4H)，3.38 (q，2H)， 2.94 (2s, 3H)5 2.52 (m, 1H), 2.38 (m, lH),2.15(m, 1H) 136 521.3 523.3 (CD3OD) 8.81 (d5 1H), 8.43 (d, 1H)S 8.27 (s, 1H), 8.11 (ddd, 1H), 7.88 (s, 1H)S 7.54 (dd, 1H), 7.28 (dd, 1H)S 6.87 (d5 1H)S 6.84 (d, 1H), 6.81 (s, 1H), 4.42 (q, 2H)S 3.78 (s, 3H), 2.50 (br s, 3H), O:\90\90896.DOC -83- 1334416 化合物編號I- M-l (obs) M+l (obs) ^NMR 2.00 (d，3H)，1.41 (t，3H) 137 522.6 524.2 (CD3OD) 8.90 (d，1H)，8.81 (d，1H)， 8.49 (dd，1H)，8.41 (s，1H)，8.06 (s，1H)， 7.84 (dd, 1H), 7.29 (dd, 1H), 6.99 (br s, 1H)，6.92 (s，1H)，6.87 (d，1H)，6.84 (d， 1H)，6.81 (s，1H)，4.42 (q，2H)，3.78 (s， 3H), 2.50 (br s, 3H), 2.00 (d, 3H), 1,41 (t，3H) 138 525 527 1.2(t.3H). 1.5(d，3H)， 3.73(s，3H)，4.3(q，2H)，5.13(m，lH)， 6.8(d，lH)，7.0(m，2H)， 7.24(t，lH)，7.53(t，lH), 7.93(s，lH)， 8.24(s，lH)，8.32(m，2H)， 8.4(s，lH)，9.08(s，lH)，11.79(bs，lH), 12.18(s,lH). 139 522.5 524.2 (CD3OD): 8.86 (d, 1H), 8.74 (d, 1H)S 8.41 (dd, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.78 (dd, 1H), 7.28 (dd, 1H), 6.85 (ds 1H), 6.83 (d, 1H), 6.80 (s, 2H),m 6.76 (s, 1H), 4.41 (qs 2H), 3.77 (s5 3H), 2.41 (br s, 3H), 1.97 (d? 3H), 1.41 (t, 3H) 140 499 501 - 141 425.3 427.2 (CD3OD) 8.8(d5lH)5 8.35(d,lH), 8.2(s, 1H), 8.i(t, 1H), 8.0(s,lH),7.9(d, 1H), 7.8(s, 1H)5 7.65-7.7(dd, 1H), 7.5(t, 1H), 7.49(d，lH)，4.6(s，2H)，4.45(s，1H)， 3.4(q，2H)，3.2(s，3H)，3.15(s，1H)，1.2(t， 3H) 142 426.3 428.2 (CD3OD): 8.8(d，lH)，8.6(d，lH)，8.3(m， 2H)，8.1(s，1H)，8.0(d，lH)，7.9(s，1H)， 7.7(d，1H)， 4.6(s, 2H), 4.45(s, 1H)S 4.4-4.5(¾ 2H), 3.3(s, 3H)S 3.15(s, 1H), 1.4(t，3H) 143 498 500 - 144 497 499 (CD3OD) 1.42(t,3H), 1.84(d.3H)，4.49(q，2H)，6.43(q，lH). 7.58(t，lH), 8.03(t，lH)， 8.08(s,lH0,8.23(d,lH), 8.67(t,lH), 8.73(5,111),8.39((1,211), 8.88(d32H),9.06(s,2H). O:\90\90896.DOC -84- 1334416 化合物编號I- M-l (obs) M+l (obs) 'HNMR 145 457 459 (CD3OD) l_4(t，3H)，3.48(d，4H)， 3.99(s，4H)，4.41(s，2H)，7.7(d，lH)， 8.07(s，lH) 8.05(m，3H)，8.73(s，lH)， 8.9(s，lH)，9.12(s，lH). 146 - 502.21 (CD3OD) 8.89 (s，1H)，8.49 (d，1H)，8.45 (s，1H)，8.22 (d，1H)，8.11 (d，1H)，8.06 (s5 1H), 7.47 (br d, 1H)? 7.36 (br s, 1H)3 3.91 (s, 3H), 3.68-3.89 (br m3 8H), 3.38 (q, 2H), 1.25 (t3 3H) ppm 147 - 487.2 (CD3〇D) 8.99 (s, 1H), 8.54 (d, 1H), 8.46 (ss 1H), 8.27 (d, 1H), 8.01 (s5 1H), 7.85 (br s，1H)，6.97 (br s，1H)，6.91 (br s， 1H), 4.47 (q，2H)，3.66-3.69 (m，5H), 3.59-3.62 (m, 2H), 2.01-2.06 (m, 2H), 1.96-2.00 (m, 2H), 1.43 (t, 3H) ppm 148 375 377 (CD3OD): 9.02(t, 2H), 8.98 (s, 2H), 8.82(d, 1H), 8.05 (d, 1H), 7.54 (t, 1H), 4.48(q, 2H)S 1.44(t, 3H) 149 - 486.22 (CD3OD) 8.98 (s, 1H), 8.44 (m, 1H), 8.38 (br s? 1H), 8.19 (brd, 1H), 8.02 (br s, 1H), 7.98 (br Sj 1H), 7.15 (br s, 1H), 7.13 (br ss 1H), 3.79 (br s, 3H), 3.67 (m, 2H), 3.61 (m, 2H), 3.37 (q, 2H), 2.05 (m, 2H), 2.00 (m, 2H), 1.25 (t, 3H) p 150 494.3 496.2 (CD3OD) 9.0(ds 2H)S 8.8(ss 1H)S 8.6(d, 1H), 8.2(t? 1H), 7.95(s, lH),7.8(d? 1H), 7.65(t, 1H), 7.5(t, 1H), 6.9(s, 1H), 6.6(s, 1H)，6.1(m，lH)，4.4(q，2H)，2.7(s, 3H), 2.05(d, 3H), 1.4(t,3H) 151 493.4 495.2 (CD3OD) 8.95(d, 2H)S 8.6(s, 1H), 8.5(d, 1H)3 8.1(t, 1H), 7.8(s, lH),7.7(d, 1H), 7.5(t, 1H)S 7.4(ts 1H), 6.8(s5 1H), 6.6(s, 1H), 6.0(m, lH),3.35(qs 2H)S 2.6(s? 3H)? 2.0(d, 3H), 1.2(t, 3H) 152 - 462.21 (CD3OD) 8.90 (d, 1H), 8.81 (d, 1H)5 8.49 (m, 1H)S 8.39 (d, 1H), 8.04 (d, 1H)3 7.85 (m, 1H)S 7.02 (br s, 1H), 6.90 (d, 1H), 4.82 (m, 1H, underneath water peak), 4.42 (q? 2H)S 4.29 (m, 1H), 3.72 (m5 1H)S 3.35 (s, 3H), 2.65 &amp; 2.90 (s， 3H)，1 153 504.3 506.3 12.14 (s, 1H); 11.11 (ss 1H); 9.59 (s, O:\90\90896.DOC -85- 1334416 化合物編號I- M-l (obs) M+l (obs) *HNMR 1H); 9.08 (d, 2H); 8.38 (s, 1H); 8.33 (ds 1H); 8.22 (s, 1H); 7.95 (d, 1H);7.56 (dd, 1H); 4.32 (q, 2H); 4.12 (br. s5 4H); 3.62 (br. s, 4H); 2.46 (br. s, 2H); 1.31 (dd, 2H); 1.22 (t, 3H). 154 474.3 476.3 10.31 (s, 1H); 9.09 (d, 2H); 8.79 (s; 1H); 8.44(s, 1H); 8.42 (s5 1H); 8.00 (s, 1H); 7.68 (t, 2H); 7.7-6.6 (br. s, 3H); 4.32(q, 2H); 3.55 (m, 4H); 3.12 (m, 4H); 2.34 (s, 6H); 1.32 (t, 3H). 155 479.3 481.2 1.33 (ts3H) 2.36(s,3H) 4.35(q,2H) 5.60(s,2H) 6.84(s31H) 6.88(s,1H) 7.68(t5lH)7.81(ds2H) 7.99(s,lH) 8.26(tslH) 8.35(s,lH)8.78(d,lH) 8.89(d，3H) 11.75 (brs，2H) 156 - 461.22 (CD3OD) 8*83 (m, 1H), 8.44 (d, 1H), 8.25 (d, 1H), 8.12 (m, 1H), 7.88 (d, 1H), 7.54 (m，1H)，6.70 (s，1H)，6·68 (s，1H)， 4.68 (m，1H)，4.32 (m，1H)，3.70 (m, 1H), 3.38 (q, 2H), 3.35 (s, 3H), 2.56 (s, 3H), 1.60 (d, 3H), 1.24 (t, 3H) ppm 157 486.3 488.3 (CD3OD) l,37(t,3H) 1.57(m,4H) 2.27(m，lH) 2.82(s，3H) 3.41(t，2H) 3.96(ds2H)4.29(d,2H) 4.43(qs2H) 7.27(s，lH) 7.50(s，lH) 7.90(t，lH) 8.17(s,lH) 8.55(s,lH) 8.659(t,lH) 8.95(d，lH)9.09(d，lH) 158 474.3 476.3 (CD3OD) 1.08(d,6H) 1.42(t3H) 2.76(s,3H)3.57(m,lH) 2.82( t，2H)4.42(m，4H) 6.98(s，lH) 7.05(s,lH) 7.86(t,lH) 8.09(s,lH) 8.41(s,lH)8.51(t,lH)8.82(dslH) 8.91(d，lH) 159 458 460 (CD3OD) 1.43(t，3H)，3.48(bs，24H)， 3.99(bs，4H)，4.48(1，2H)，4.63(s，2H)， 7.55(t，lH)，7.71(d，lH)，8.1(s，lH)， 8.33(d5lH), 8.9(1H), 9.03(d,2H), 9.13(s.lH). 160 457 459 (CD3OD) 1.35(t，3H)，3.3-3.5(m，6H)， 3-99(bs，4H)，4.62(s，2H)， 7.52(t，lH)，7/7(cUH)，8.08(s，lH)， 8.32(d，lH)，8_88(s，lH)， O:\90\90896.DOC -86- 1334416 化合物編號I- M-l (obs) M+l (obs) lH NMR 9.05(d，2H)9.1(s，lH). 161 446.28 448.2 1.2 (t，3H)，3·2 (m，2H)，3.3 (br s，4H)， 3,9 (br s，4H)，4.7 (s，2H)，7.7 (s，1H)， 7.8 (brs，1H)，7.95 (m，1H)，8.1 (s，1H)， 8.25 (s, 1H), 8.7 (m, 1H), 8.8 (m; 1H)5 9.2 (s, 1H), 10.6 (brs, 1H) 162 550.3 552.3 12.32 (s5 1H); 11.18 (s, lH);9.08(d, 2H); 8.62 (s，1H); 8.39 (s，1H); 8.37 (s， 1H); 7.98 (s, 1H); 7.62 (m, 2H); 7.58 (dd? 1H); 7.48 (m, 3H); 6.4-5.9 (br. s, 3H); 4.38 (s, 2H); 4.33 (q, 2H); 3.42 (m, 4H); 3.15 (m, 4H); 1.35 (t, 3H). 163 501.3 503.3 (CD3OD) 9.1(d, 1H), 8.8(t, 1H), 8.5(ds 1H)S 8.4(s, 1H), 8.3(s, 1H), 8.2(ts 1H), 7.7(s, 1H)S 7.5(s, 1H); 4.8(t, 2H), 4.4(q, 2H)，4.1(d，2H)，3.9(t，2H)，3.75(d，2H)， 3.7(t, 2H), 3.4(m, 2H), 3.3(s, 2H), 2.85(s, 3H), 2.0(s5 5H)s 1.4(t, 3H) 164 500.4 502.3 (CD3OD) 8.75(d, 1H), 8.3(d, 1H)5 8.2(s, 1H)，8.0-8.05(t，1H), 7.8 (s, 1H)，7.5(t, 1H)，6.8(s，1H)，6.7(s，1H)，4.5-4.6(t， 2H)，4.0(brd s，4H)，3.5-3.6(t，4H)，3.4(q， 2H)，3.3(t，2H)，2.6(s，3H)，1.2-1.3(t，3H) 165 474 476 (CD3OD) 9.04(ds 1H), 8.71(d, 1H), 8.34(d, 1H), 8.23(dd, 1H), 7.94 (d, 1H), 7.84(m，1H)，7.65(d，1H)，7_57(m，1H)， 4,56(s，2H)，3.98(t，4H)，3.45(t，4H)， 3.37(q，2H)，1.24(t，3H) 166 475 477 (CD3OD): 9.07(d, 1H), 8.72(ds 1H), 8.49(d，1H)，8.28(dd，1H)，8.04 (d，1H)， 7.92(m5 1H), 7.69(d, 1H), 7.63(ra, 1H)5 4,63(s，2H)，4.47(q，2H)，3.99(m，4H)， 3.44(m,4H), 1.43(t, 3H) 167 522.3 524.4 (CD3OD) 8.94 (d, 2H), 8.65 (s, 1H), 7.85 (s, 1H), 7.44 (dd, 1H), 7.27 (dd, 1H), 6.84 (d, 2H)3 6.80 (s, 1H)S6.70 (s, 1H), 6.64 (s, 1H), 3.77 (s, 3H), 3.36 (q, 2H)S 2.39 (brs, 3H), 1.96 (d, 3H), 1.24 (ts 3H) 168 - 474.3 (CD3OD) 1.45(t,3H) 1.80(ds3H) 2.69(m52H) 3.50(m,2H) 3.97(m54H) 4.49(q,2H) 4.72(mslH)7.55(t,lH) 7.71(d,lH) 1.15(s,lH) 8.33(d5lH)O:\90\90896.DOC 78- 1334416 Compound No. I-Ml (obs) M+l (obs) *HNMR 91 429.2 431.2 (CD30D): 8.97 (s3 1H); 8.89 (d, 1H); 8.49 ( d, 1H); 8.37 (m, 2H); 8.22 (ddd, 1H); 7.93 (d, 1H); 7.64 (dd, 1H); 3.38 (q, 2H); 2.91 (m, 1H); 1.25 (t , H): 0.88 (m, 2H); 0.67 (m, 2H). 92 360.13 362.19 1.15 (t, 3H), 3.25 (m, 2H), 3.9 (s, 3H), 7.15 (m, 1H), 7.65 (m,1H), 7.8 (s5 1H), 8.0 (s, 1H), 8.2 (m, 1H), 8.3 (m, 1H)S 8.65 (m,1H),9_0 (m,2H),10.3 (br s, 1H) 93 371 373 1.12(t,3H), 3.25(m,2H),4.2(bs,2H), 7.0.2-7.25(m,lH),7.5(m,1H), 7.81(m, lH), 8.08 (t, lH), 8.22 (m, lH), 8.61-8.48 (m, 2H), 8.4 (d, lH), 8.46 (s5lH). 94 430 432 0.92 (ά, 6Η), 1.12 ( m, 3H), 2.23 (m.lH), 2.83 (d, 2H), 3.35 (m, 2H), 7.5 (m, lH), 7.61 (bs, lH), 7.89 (s, lH), 8.1 (m) , lH), 8.4 (s, lH), 8.58 (m, lH), 8.78 (bs, lH), 8.3 (d, lH). 95 431.03 433.2 (CD3OD) 1.2 (7, 3H), 3.3 (q, 2H ), 3.8 (m, 2H), 4.6 (m, 2H), 7.4 (m, 1H), 7.8 (m, 1H), 8.0 (s, 1H) 5 8.3 (m, 2H); 8.5 (m, lH) , 8.7 (m, 2H), 9.1 (s lH) 96 507.2 509.2 (CD3OD): 8.9(d, 1H)? 8.55(d, 1H), 8.4(s,1H), 8.3(m,lH),8.0(s,lH),7.7(m, 1H) , 7.3(t, 1H), 7.0(s, 2H), 6.85(d, 1H), 6.7 (d, 2H)s5.5(s, 2H), 3.7(s, 3H)? 3.3(q, 2H) ?2.5(s, 3H), 1.25 (t, 3H) 97 401 403 9.1 (s, 1H), 8.6 (d, 2H)S 8.3 (m, 1H)? 8.1 (s, 1H)5 7.9 (s, 1H ) S 7.8 (s5 1H) 7.5 (m5 1H), 7.0 (dslH), 4.3 (m? 2H), 3.3 (m, 2H), 1.4 (t, 3H)S 1.1 (t, 3H). 98 497.03 499.18 , U6(t,3H)3.25(q,2H)4.44(d,2H) 7.17(t,2H) 7.38(t,2H)7.53(t,lH) 7.79(mslH) 7.87(s,lH) 8.10(t, lH) 8.32(s,lH)8.51(s,lH) 8.57(d,lH) 8.77(s,lH)8.82(d,lH) 8.94(t,lH)11.10(br sJH) 99 432 434 - O:\ 90\90896.DOC -79- 1334416 Compound No. I- Ml (obs) M 十 1 (obs) *HNMR 100 418.25 420.15 1.1 (t, 3H), 3.2 (m5 2H), 3.95 (s, 3H), 4.1 ( s, 2H), 7.2 (br s, 1H), 7, 25 (brs, 1H), 7.9 (ss 1H), 8.2 (m? 1H), 8.25 (s, 1H), 8.7 (d, 1H), 9.05 (s5 2H)? 10.4 (br s, 1H) 101 431 433 8.65 (d, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 7.98 (d, 1H), 7.78 (d, 1H), 7.38 (m,1H), 6.93 (s5 1H), 6.89 (dd, 1H), 4.51 (q, 2H)5 3.63 (s, 3H), 3.35 (q, 2H), 1.55 (t, 3H), 1.22 (t, 3H) 102 375 377 8.86 (d, 1H), 8.69 (m , 1H), 8.52 (d, 1H), 8.16 (m, 2H), 7.79 (m, 2H), 7.56 (m, 1H), 7.50 (m, 1H), 3.55 (m? 2H) 1.23S (t, 3H) 103 430 432.1 8.87 (br. s, 1H); 8.81 (d, 1H); 8.66 (br. s·, 1H); 8.49 (s, 1H); 8.39 (br. s·, 1H); 8.25 ( d, 1H); 8.09 (ddd, 1H); 7.87 (d, 1H); 7.52 (dd, 1H); 5.3 (very br. s, 5 H); 4.29 (q, 2H); 2.85 (iti, 1H) 1.31 (t, 3H); 0.72 (m, 2H); 0.63 (m, 104 417.19 419.14 il (t, 3H), 3.2 (q, 2H), 3·45 (s, 3H), 4.1 (s, 3H) ), 6.7 (dd, 1H), 6.85 (d, 1H), 7.15 (br s, 1H), 7.35 (br s, 1H), 7.8 (d, 1H), 7.95 (s, 1H), 8.2 (s, 1H), 8.4 (br s, 1H), 8.7 (d, 1H), 10.5 (brs, 1H) 105 406 408 8.97 (br. s, 2H); 8.60 (d, 1H); 7.99 (br. s., 1H); 7.96 (m, 1H); 7.81 (br. s., 1H); 7.57 (m, 1H); 3.98 (s, 3H); 3.25 (m, 2H); 1.11 (t, 3H). 106 508.2 510.2 1·1 (t,3H), 2.4 (s,3H),3.2 (q, 2H), 4_1 (s3 3H), 5.4 (s, 2H), 6.65 (s5 1H), 6.75 (s, 1H), 7.15 (b Rs, 1H)S 7.3 (m, 2H), 7.35 (m, 1H), 7.8 (m, 1H), 7.95 (s, 1H), 8.25 (s5 1H), 8.35 (br s5 1H)5 8.5 (ms 1H ), 8.75 (m, 1H), 10.5 (brs, 1H) 107 495.2 497.2 8.8 (m3 1H), 8.2 (ms 1H), 7.9 (s, 1H), 7.8 (m, 1H), 7.4 (m, 2H) ,7,35(d,2H), 7.25(d,2H),6.7-6.8(m,2H),5.3(2, 2H), 4.0 (m, lH), 3.4(q? 2H), 2.4(ss 3H), Ll(t, 3H) 108 417 419 9.12 (br. s, 1H); 8.60 (d, 1H); 8.39 (m, 1H); 8.36 (s, 1H); 8.25 (s, 1H); 7.89 (s, 1H); 7.70 (dd, 1H); 7.41 (m, 1 H); 4.13 (s, 3H); 3.98 (s, 3H); 3.26 (m, 2H); 1.15 (t, 3H). :\9O\90896.DOC -80- 1334416 Compound No. I- Ml (obs) M+l (obs) ^NMR 109 358.3 360.1 (CD30D) 9.61 (d, 1H), 9.22 (d? 1H), 8.83- 8.79 (m5 3H)? 8.65 (d, 1H)S S.47 (d, 1H), 8.02 (dd, 1H)S 8.00 (s, 1H), 3.37 (q5 2H)S 1.24 (t, 3H) 110 388.3 390.2 (CDCI3) 14.05 (br s, 1H)S 12.85 (br s, 1H), 8.37 (t, 1H), 7.97 (d, 1H), 7.88 (ds 1H), 7.79-7.74 (m, 2H), 7.63 (dd, 1H), 7.46 (d, 1H), 6.62 (dd, 1H), 5.75 (br s, 1H), 3.45-3.40 (m, 2H), 1.27 (t, 3H) 111 492.3 494.1 10.3(s, lH), 8.9 (d, lH ); 8.6 (m, lH), 8.5 (d, lH), 8.2 (s, lH), 8.05 (t, lH), 7.8-7.9 (m? 2H), 7.5 (m, 2H), 7.4 (d, lH), 7.3(m,lH)s6.7(s,lH), 6.6(s,lH), 3.3(q,2H)3 1.9(d,3H), ll-1.2(t,3H). 112 475.2 477.2 10.62 (s, 1H); 8.74 (d, 1H); 8.65 (s, 1H); 8.40 (s, 1H); 8.28 (s, 1H); 8.23 (s, 1H); 7.87 (s, 1H); 7.43 (s, 1H); 7.32 (ms 2H); 5.52-4.41 (br. s, 3H); 4.10 (s, 3H); 3.24 (dt, 2H); 1.41 (s, 9H); 1.13 (t, 3H) 113 494.2 496.2 (CD3OD) 9.06 (s, 1H); 8.93 (d, 1H); 8.71 (d, 1H); 8.50 (m, 2H); 8.39 (s, 1H); 8.00 (s, 1H); 7.87 (dd, 1H); 7.42 (d5 2H); 7.35 (dds 2H); 7.25 (dd, 1H); 5.27 (q, 1H); 4.41 (q, 2H); 1.62 (d, 3H); 1.42 (t , 3H) 114 370.2 372.2 12.09 &amp; 12.74 (s, 1H), 10.25 &amp; 9.94 (s, 1H), 9.12 &amp; 8.94 (s, 1H), 8.35-6.58 (m, 9H), 3.24 (m, 2H) ), 1.13 (t, 3H) 115 442.1 444.3 (CD3OD) 8.65 (d, 1H), 7.94 (s, 1H), 7.91 (d, 1H), 7.72 (d, 2H), 7.66 (s, 1H), 7.40 (d, 2H), 6.63 (dd, 1H), 4.52 (s, 2H)S 3.40 (t, 2H), 3.35 (q, 2H), 2.47 (t, 2H), 2.09-2.03 (m, 2H), 1.24 (t, 3H) 116 382 384 - 117 415 41 7 9.17 (br. s7 1H); 9.0 (m, 1H); 8.98 (d, 1H); 8.72 (d, 1H); 8.55 (m, 1H); 8.38 (s, 1H); 7.94 (s, 1H) 7.86 (d, 1H); 7.79 (m, 1H); 3.97 (s, 3H); 3.27 (m, 2H); 1.15 (t, 3H). 118 401 403 - 119 403.3 405.2 (CD3OD): 8.78 (s , 1H), 8.67 (d, 1H), O:\90\90896.DOC -81 · 1334416 Compound No. I- Ml (obs) M+l (obs) 'HNMR 8.37 (d,1H), 8.24 (d, 1H), 8.22 (s, 1H), 8.04 (d, 1H), 7.91 (s, 1H), 7.67 (dd, 1H), 7.40 (dd, 1H), 4.22 (s, 3H), 3.34 (q, 2H) ), 1.23 (t, 3H) 120 434.32 436.23 1·1 (t, 3H), 2.8 (s, 6H), 3.2 (m, 2H), 3.4 (s, 3H), 4.6 (s, 2H), 6.6 ( d,1H), 6.8 (s, 1H), 7.2 (br s5 1H), 7.6 (s, 1H), 7.8 (d, 1H), 7.9 (s, 1H), 7.95 (s, 1H), 10.0 (br s, lH), 10.2 (brs, lH) 121 414 416 (CD3OD): 9.40 (br. s, 1H); 9.07 (d, 1H); 8.98 (d, 1H); 8.91 (d, 1H); 8.80 ( s, 1H); 8.60 (s; 1H); 8.24 (dd, 1H); 8.11 (d, 1H); 7.84 (dd, 1H); 3.35 (m, 2H); 3.01 (s, 3H); 1.25 (t , 3H). 122 415 417 - 123 435.28 43726 1.3 (t, 3H)? 2.8 (s, 6H), 3.5 (s, 3H), 4.2 (q, 2H), 4.6 ( s, 2H), 6.6 (dd, 1H), 6.7 (s, 1H), 7.7 (s, 1H), 7.8 (d, 1H), 8.0 (m, 2H), 10.1 (brs, 1H), 11.7 (brs , 1H) 124 431.2 433.2 9.28 (s, 1H); 9.08 (d, 1H); 8.8-7A (v. broad s, 4H); 8.67 (s5 1H); 8.53 (s, 1H); 8.46 (d, 1H 8.05 (d, 1H); 7.59 (dd, 1H); 4.33 (q, 2H); 2.88 (m, 1H); 2.35 (s, 6H); 1.34 (t, 3H); 0.76 (m, 2H) 0.61 (ms 2H). 125 447.4 - 9.10 (s, 1H); 8.60 (d, 1H); 8.47 (m, 2H); 7.95 (s5 1H); 7.83 (s, 1H); 7.12 (d, 1H) ; 5.2-3.6 (br. m, 7H); 2.86 (M, 1H); 1.30 (t, 3H); 0.75 (m, 2H); 0.64 (m, 2H) 126 439.2 441.2 (CDCI3) 13.89 (br s, 1H), 12.89 (br s, 1H), 8.28 (d, 1H)5 8.25 (d, 1H), 7.96 (d, 1H), 7.74 (s, 1H), 7.69-7.43 (m, 6H), 7.40 ( Ss 1H), 6.64 (dd, 1H), 6.11 (br s5 1H), 3.46-3.40 (m, 2H), 1.27 (t, 3H) 127 418.2 420.2 (CD3OD) 9.72 (d, 1H)S 8.87 (d, 1H), 8.82 (d, 1H), 8.11 (d, 1H), 8.09 (d, 1H), 7.85 (d, 1H), 7.39 (d, 1H), 7.36 (d, 1H), 4.43 (q, 2H) ), 3.35 (q, 2H), 1.44 (t, 3H), 1.24 (t, 3H) 128 449.8 452.1 (CD3OD) 9.21 (d, 1H), 8.83 (ddd, 1H)S 8.81 (dd, 1H) S 8. 68 (d, 1H), 8.26 (d5 1H), 8.18 (d, 1H), 8.07 (dd, 1H), 8.05 (d, 1H), 7.50 (dd, 1H), 3.36 (q, 2H), 3.34 ( s,3H), O:\9O\90896.DOC -82- 1334416 Compound No. I- Ml (obs) M+l (obs) 'HNMR 1.23 (t, 3H) 129 - - 9.31 (s, 1H); 9.08 (d, 2H); 8.63 (s, 1H); 8.43 (d, 1H); 8.02 (d, 1H); 7.89 (s5 1H); 7.57 (t5 1H); 8.8-6.6 (very br. s, 4H) 4.31 (q, 2H); 2.32 (s, 6H); 1.42 (s, 9H); 1.33(t, 3H). 130 495.4 497.2 9.07 (d, 2H); 8.73 (d, 1H); 8.56 (s, 1H); 8.44 (d, 1H); 8.03 (d, 1H); 7.57 (t, 3H); 7.44 (d, 2H); 7.36 (dd, 2H); 7.26 (dd, 1H); 6.95-5.90 (very Broad s., 5H); 5.18 (dt, 1H); 4.32 (q5 2H); 2.32 (s5 6H); 1.53 (d5 3H); 1.33(t, 3H). 131 432 434 (CD3OD) 1.08(d,6H ), 1.43(t,3H), 2,33(m,lH), 2.91(d,2H), 4.45(q,2H), 7.53(t,lH),8.08(s,lH), 8.79(s, lH) &lt;8.94(s,lH), 9.05(d,2H), 9.5(s,lH). 132 514.23 516.23 8.84 (d, 1H), 8.81-8.83 (m; 1H), 8.35 (s5 1H), 8.06 (dd, 1H), 7.90 (dd, 1H), 7.80 (d, 1H), 6.80 (br s5 1H), 6.70 (d, 1H), 4.30 (q, 2H), 3.42-3.54 (m , 4H), 3.48 (s, 3H), 3.12-3.17 (m, 4H), 2.81 (d, 3H), 132 (t, 3H) ppm 133 501.33 503.26 - 134 521.6 523.2 (CD3OD) 8.82 (s, lH) , m 8.46 (d, 1H), 8.30 (s, 1H), 8.13 (dd, 1H), 7.90 (s, 1H), 7.55 (dd, 1H), 7.28 (dd, 1H), 6.86-6.77 (m, 4H), 6.74 (s, 1H), 3.77 (s, 3H), 3.36 (q, 2H), 2.41 (br s, 3H), 1.97 (d, 3H), 1.24 (t, 3H) 135 470.3 472.5 (CD3OD 8.85 (br s, 1H), 8.45 (d, 1H), 8.34 (dd, 1H), 8/26 (dd, 1H), 8.13 (ddds 1H), 7.96 (dd, 1H), 7.56 (dd, 1H) ), 7.43 (dds 1H), 7.29 &amp; 7.20 (ss 1H), 5.49 (m, 1H), 3.66-3.25 (m, 4H), 3.38 (q, 2H), 2.94 (2s, 3H)5 2.52 (m , 1H), 2.38 (m, lH), 2.15 (m, 1H) 136 521.3 523.3 (CD3OD) 8.81 (d5 1H), 8.43 (d, 1H)S 8.27 (s, 1H), 8.11 (ddd, 1H), 7.88 (s, 1H)S 7.54 (dd, 1H), 7.28 (dd, 1H)S 6.87 (d5 1H)S 6.84 (d, 1H), 6.81 (s, 1H), 4.42 (q, 2H)S 3.78 ( s, 3H), 2.50 (br s, 3H), O:\90\90896.DOC -83- 1334416 Compound No. I- Ml (obs) M+l (obs) ^NMR 2.00 (d,3H),1.41 ( t,3H) 137 522.6 524.2 (CD3OD) 8.90 (d,1H),8.81 (d,1H) , 8.49 (dd, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.84 (dd, 1H), 7.29 (dd, 1H), 6.99 (br s, 1H), 6.92 (s, 1H) , 6.87 (d, 1H), 6.84 (d, 1H), 6.81 (s, 1H), 4.42 (q, 2H), 3.78 (s, 3H), 2.50 (br s, 3H), 2.00 (d, 3H) , 1,41 (t,3H) 138 525 527 1.2(t.3H). 1.5(d,3H), 3.73(s,3H),4.3(q,2H),5.13(m,lH), 6.8(d , lH), 7.0 (m, 2H), 7.24 (t, lH), 7.53 (t, lH), 7.93 (s, lH), 8.24 (s, lH), 8.32 (m, 2H), 8.4 (s, lH), 9.08 (s, lH), 11.79 (bs, lH), 12.18 (s, lH). 139 522.5 524.2 (CD3OD): 8.86 (d, 1H), 8.74 (d, 1H)S 8.41 (dd, 1H ), 8.35 (s, 1H), 7.99 (s, 1H), 7.78 (dd, 1H), 7.28 (dd, 1H), 6.85 (ds 1H), 6.83 (d, 1H), 6.80 (s, 2H), m 6.76 (s, 1H), 4.41 (qs 2H), 3.77 (s5 3H), 2.41 (br s, 3H), 1.97 (d? 3H), 1.41 (t, 3H) 140 499 501 - 141 425.3 427.2 (CD3OD ) 8.8(d5lH)5 8.35(d,lH), 8.2(s, 1H), 8.i(t, 1H), 8.0(s,lH),7.9(d, 1H), 7.8(s, 1H)5 7.65-7.7(dd, 1H), 7.5(t, 1H), 7.49(d,lH), 4.6(s,2H),4.45(s,1H), 3.4(q,2H),3.2(s,3H) , 3.15 (s, 1H), 1.2 (t, 3H) 142 426.3 428.2 (CD3OD): 8.8 (d, lH), 8.6 (d, lH), 8.3 (m, 2H), 8.1 (s, 1H), 8.0 (d, lH), 7.9 (s, 1H), 7.7 (d,1H), 4.6(s, 2H), 4.45(s, 1H)S 4.4-4.5(3⁄4 2H), 3.3(s, 3H)S 3.15(s, 1H), 1.4(t,3H) 143 498 500 - 144 497 499 (CD3OD) 1.42(t,3H), 1.84(d.3H), 4.49(q,2H),6.43(q,lH). 7.58(t,lH), 8.03(t,lH), 8.08 (s, lH0, 8.23 (d, lH), 8.67 (t, lH), 8.73 (5, 111), 8.39 ((1,211), 8.88 (d32H), 9.06 (s, 2H). O:\90\90896. DOC -84- 1334416 Compound No. I- Ml (obs) M+l (obs) 'HNMR 145 457 459 (CD3OD) l_4(t,3H), 3.48(d,4H), 3.99(s,4H),4.41 (s, 2H), 7.7 (d, lH), 8.07 (s, lH) 8.05 (m, 3H), 8.73 (s, lH), 8.9 (s, lH), 9.12 (s, lH). 146 - 502.21 (CD3OD) 8.89 (s, 1H), 8.49 (d, 1H), 8.45 (s, 1H), 8.22 (d, 1H), 8.11 (d, 1H), 8.06 (s5 1H), 7.47 (br d, 1H) ) 7.36 (br s, 1H)3 3.91 (s, 3H), 3.68-3.89 (br m3 8H), 3.38 (q, 2H), 1.25 (t3 3H) ppm 147 - 487.2 (CD3〇D) 8.99 (s , 1H), 8.54 (d, 1H), 8.46 (ss 1H), 8.27 (d, 1H), 8.01 (s5 1H), 7.85 (br s, 1H), 6.97 (br s, 1H), 6.9 1 (br s, 1H), 4.47 (q, 2H), 3.66-3.69 (m, 5H), 3.59-3.62 (m, 2H), 2.01-2.06 (m, 2H), 1.96-2.00 (m, 2H) , 1.43 (t, 3H) ppm 148 375 377 (CD3OD): 9.02(t, 2H), 8.98 (s, 2H), 8.82(d, 1H), 8.05 (d, 1H), 7.54 (t, 1H), 4.48(q, 2H)S 1.44(t, 3H) 149 - 486.22 (CD3OD) 8.98 (s, 1H), 8.44 (m, 1H), 8.38 (br s? 1H), 8.19 (brd, 1H), 8.02 ( Br s, 1H), 7.98 (br Sj 1H), 7.15 (br s, 1H), 7.13 (br ss 1H), 3.79 (br s, 3H), 3.67 (m, 2H), 3.61 (m, 2H), 3.37 (q, 2H), 2.05 (m, 2H), 2.00 (m, 2H), 1.25 (t, 3H) p 150 494.3 496.2 (CD3OD) 9.0(ds 2H)S 8.8(ss 1H)S 8.6(d, 1H), 8.2(t? 1H), 7.95(s, lH), 7.8(d? 1H), 7.65(t, 1H), 7.5(t, 1H), 6.9(s, 1H), 6.6(s, 1H) ), 6.1 (m, lH), 4.4 (q, 2H), 2.7 (s, 3H), 2.05 (d, 3H), 1.4 (t, 3H) 151 493.4 495.2 (CD3OD) 8.95 (d, 2H)S 8.6 (s, 1H), 8.5(d, 1H)3 8.1(t, 1H), 7.8(s, lH), 7.7(d, 1H), 7.5(t, 1H)S 7.4(ts 1H), 6.8(s5 1H), 6.6(s, 1H), 6.0(m, lH), 3.35(qs 2H)S 2.6(s? 3H)? 2.0(d, 3H), 1.2(t, 3H) 152 - 462.21 (CD3OD) 8.90 (d, 1H), 8.81 (d, 1H)5 8.49 (m, 1H)S 8.39 (d, 1H), 8.04 (d, 1H)3 7.85 (m, 1H)S 7.02 (br s, 1H), 6.90 (d, 1H), 4.82 (m, 1H, underneath water peak), 4.42 (q? 2H)S 4.29 (m, 1H), 3.72 (m5 1H)S 3.35 (s, 3H), 2.65 &amp; 2.90 (s, 3H), 1 153 504.3 506.3 12.14 (s, 1H); 11.11 (ss 1H); 9.59 (s, O:\90\90896.DOC - 85- 1334416 Compound No. I-Ml (obs) M+l (obs) *HNMR 1H); 9.08 (d, 2H); 8.38 (s, 1H); 8.33 (ds 1H); 8.22 (s, 1H); (d, 1H); 7.56 (dd, 1H); 4.32 (q, 2H); 4.12 (br. s5 4H); 3.62 (br. s, 4H); 2.46 (br. s, 2H); 1.31 (dd, 2H); 1.22 (t, 3H). 154 474.3 476.3 10.31 (s, 1H); 9.09 (d, 2H); 8.79 (s; 1H); 8.44 (s, 1H); 8.42 (s5 1H); 8.00 (s , (H, 4H); 3.32 (q, 2H); 1.32 (t, 3H). 155 479.3 481.2 1.33 (ts3H) 2.36(s,3H) 4.35(q,2H) 5.60(s,2H) 6.84(s31H) 6.88(s,1H) 7.68(t5lH)7.81(ds2H) 7.99(s,lH) 8.26(tslH) 8.35(s,lH)8.78(d,lH) 8.89(d,3H) 11.75 (brs,2H) 156 - 461.22 (CD3OD) 8*83 (m, 1H), 8.44 (d, 1H), 8.25 (d, 1H), 8.12 (m, 1H), 7.88 (d, 1H), 7.54 (m, 1H), 6.70 (s, 1H), 6.68 (s,1H), 4.68 (m,1H), 4.32 (m,1H), 3.70 (m, 1H), 3.38 (q, 2H), 3.35 (s, 3H), 2.56 (s, 3H), 1.60 ( d, 3H), 1.24 (t, 3H) ppm 157 486.3 488.3 (CD3OD) l,37(t,3H) 1.57(m,4H) 2.27(m,lH) 2.82(s,3H) 3.41(t,2H) 3.96(ds2H)4.29(d,2H) 4.43(qs2H) 7.27(s,lH) 7.50(s,lH) 7.90(t,lH) 8.17(s,lH) 8.55(s,lH) 8.659(t,lH) 8.95(d,lH)9.09(d,lH) 158 474.3 476.3 (CD3OD) 1.08(d,6H) 1.42(t3H) 2.76(s,3H)3.57(m,lH) 2.82( t,2H)4.42(m, 4H) 6.98(s,lH) 7.05(s,lH) 7.86(t,lH) 8.09(s,lH) 8.41(s,lH)8.51(t,lH)8.82(dslH) 8.91(d,lH) 159 458 460 (CD3OD) 1.43 (t, 3H), 3.48 (bs, 24H), 3.99 (bs, 4H), 4.48 (1, 2H), 4.63 (s, 2H), 7.55 (t, lH), 7.71 (d, lH), 8.1 (s, lH), 8.33 (d5lH), 8.9 (1H), 9.03 (d, 2H), 9.13 (s.lH). 160 457 459 (CD3OD) 1.35 (t, 3H), 3.3-3.5 (m,6H), 3-99(bs,4H), 4.62(s,2H), 7.52(t,lH),7/7(cUH),8.08(s,lH), 8.32(d,lH), 8_88(s,lH), O:\90\90896.DOC -86- 1334416 Compound No. I-Ml (obs) M+l (obs) lH NMR 9.05(d,2H)9.1(s,lH). 161 446.28 448. 2 1.2 (t,3H),3·2 (m,2H),3.3 (br s,4H), 3,9 (br s,4H),4.7 (s,2H),7.7 (s,1H), 7.8 (brs,1H), 7.95 (m,1H), 8.1 (s,1H), 8.25 (s, 1H), 8.7 (m, 1H), 8.8 (m; 1H)5 9.2 (s, 1H), 10.6 ( Brs, 1H) 162 550.3 552.3 12.32 (s5 1H); 11.18 (s, lH); 9.08 (d, 2H); 8.62 (s, 1H); 8.39 (s, 1H); 8.37 (s, 1H); 7.98 ( s, 1H); 7.62 (m, 2H); 7.58 (dd? 1H); 7.48 (m, 3H); 6.4-5.9 (br. s, 3H); 4.38 (s, 2H); 4.33 (q, 2H) 3.42 (m, 4H); 3.15 (m, 4H); 1.35 (t, 3H). 163 501.3 503.3 (CD3OD) 9.1(d, 1H), 8.8(t, 1H), 8.5(ds 1H)S 8.4( s, 1H), 8.3(s, 1H), 8.2(ts 1H), 7.7(s, 1H)S 7.5(s, 1H); 4.8(t, 2H), 4.4(q, 2H), 4.1(d, 2H), 3.9 (t, 2H), 3.75 (d, 2H), 3.7 (t, 2H), 3.4 (m, 2H), 3.3 (s, 2H), 2.85 (s, 3H), 2.0 (s5 5H) s s (t, 3H) 164 500.4 502.3 (CD3OD) 7.5 (t, 1H), 6.8 (s, 1H), 6.7 (s, 1H), 4.5-4.6 (t, 2H), 4.0 (brd s, 4H), 3.5-3.6 (t, 4H), 3.4 (q) , 2H), 3.3(t, 2H), 2.6(s, 3H), 1.2-1.3(t, 3H) 165 474 476 (CD3 OD) 9.04(ds 1H), 8.71(d, 1H), 8.34(d, 1H), 8.23(dd, 1H), 7.94 (d, 1H), 7.84(m,1H), 7.65(d,1H), 7_57(m,1H), 4,56(s,2H), 3.98(t,4H), 3.45(t,4H), 3.37(q,2H), 1.24(t,3H) 166 475 477 (CD3OD): 9.07(d, 1H), 8.72(ds 1H), 8.49(d,1H), 8.28(dd,1H), 8.04 (d,1H), 7.92(m5 1H), 7.69(d, 1H), 7.63(ra , 1H)5 4,63(s,2H),4.47(q,2H),3.99(m,4H), 3.44(m,4H), 1.43(t, 3H) 167 522.3 524.4 (CD3OD) 8.94 (d, 2H), 8.65 (s, 1H), 7.85 (s, 1H), 7.44 (dd, 1H), 7.27 (dd, 1H), 6.84 (d, 2H)3 6.80 (s, 1H)S6.70 (s, 1H), 6.64 (s, 1H), 3.77 (s, 3H), 3.36 (q, 2H)S 2.39 (brs, 3H), 1.96 (d, 3H), 1.24 (ts 3H) 168 - 474.3 (CD3OD) 1.45 (t,3H) 1.80(ds3H) 2.69(m52H) 3.50(m,2H) 3.97(m54H) 4.49(q,2H) 4.72(mslH)7.55(t,lH) 7.71(d,lH) 1.15(s,lH ) 8.33 (d5lH)

O:\9O\90396.DOC -87- 1334416 化合物編號I- M-l (obs) M+l (obs) 'HNMR 8.91(s，1H) 9.08(d，2H) 9.17(s，1H) 169 445.44 447.24 1.3 (ts 3H), 2.9 (br s, 6H)5 3.6 (brs, 2H), 4.3 (q, 2H), 4.6 (m, 2H), 7.1 (m, 1H)5 7.6 (ms 1H), 7.9 (s, 1H), 8.2 (m, 1H), 8.25 (s, 1H), 8.3 (ms 1H), 8.6 (d, 1H)S 8.7 (d, lH)，9.1(s，lH)，9.7(br，s，!H) 170 444.43 446.22 1.2 (t? 3H), 2.9 (br s, 6H), 3.25 (m, 2H), 3.6 (brs, 2H),4.6 (ms 2H),7.1 (m, 1H), 7.4 (br s, 1H), 7.6 (m, 1H), 7.9 (s, 1H), 8.1 (br s, 1H), 8.2 (s, 1H), 8.3 (m, 1H), 8.6 (d5 1H), 8.7 (d, 1H), 9.1 (s, 1H)5 9.8 (brs, 1H), 10.5 (brs5lH) m 460.2 462.2 (CD3OD) 8.95 (d，1H)，8.86 (d，1H)， 8.57 (dt，1H)，8.46 (d，1H)，8.17 (d，1H)， 7.93 (t，1H)，7.62 (br s 1H)，7.33 (d，1H)， 5.14 (m, 1H), 4.42 (q, 2H), 4.26 (ms 1H)S 3.75 (dd, 1H), 3.36 (s, 3H)? 2.81 (s5 3H), 1.42(d，3H)，1.30 (t，3H) ppm 172 485 487 (CD3OD) 1.45-U2(m, 3H), 1.9(m，lH)，2.1(m,2H)，2.32(m，lH)， 3.5-3.3(m，5H)，3_7(m，4H)， 3.99(bsslH), 4.4(q,2H), 4.57(bd,lH), 7.58(d，lH)，7.8(t，lH)， 8.03(s，lH0,8.32(d，lH)，8.42(m，2H)， 8.75(d，lH)，8.88(s，lH) 9‘l(s，lH). 173 484 486 (CD3OD) L15(t,3H), L4(t,3H), 3.02(8,2^1),3.6(111,2^, 3.68(m,2HX 3.95(s，2H)，4.4(m，2H)，4.61(s，2H), 7.8(m，2H)，8.08(s，lH)，8.48(m，3H), 8.78(d，lH), 8.9(d，lH)，9.17(s，lH). 174 503.2 505.2 (CDCI3) 8.94 (d, 1H)S 8.87 (d, 1H), 8.15 (d, 1H), 8.11 (d, 2H), 7.95 (ddd5 1H), 7.90 (s, 1H)? 7.70 (d, 1H), 7.42 (dd, 1H), 4.76 (s，2H), 4.46 (q，2H)，3.82 (t，4H)， 3.64 (t, 4H), 3.40 (s, 6H)S 1.45 (t, 3H) 175 593.4 595.3 10.85 (s5 1H); 8.84 (s, 1H); 8.72 (s, 1H); 8.58 (d, 1H); 8.52 (s, 1H); 8.30 (d5 1H); 8.08 (s, 1H); 7.92 (d, aH); 7.44 (d, 2H); 7.34 (dd, 2H); 7.24 (t, 1H); 6.05-4.9 (br. s); 5.21(dqs 1H); 4.78 (d, 2H); 4.31 (q? 2H);3.58(d, 2H); 3.52( 176 543.5 545.3 11.76 (s, 1H); 9.59 (s, 1H); 8.89 (d, 1H);O:\9O\90396.DOC -87- 1334416 Compound No. I-Ml (obs) M+l (obs) 'HNMR 8.91(s,1H) 9.08(d,2H) 9.17(s,1H) 169 445.44 447.24 1.3 (ts 3H), 2.9 (br s, 6H)5 3.6 (brs, 2H), 4.3 (q, 2H), 4.6 (m, 2H), 7.1 (m, 1H)5 7.6 (ms 1H), 7.9 (s , 1H), 8.2 (m, 1H), 8.25 (s, 1H), 8.3 (ms 1H), 8.6 (d, 1H)S 8.7 (d, lH), 9.1 (s, lH), 9.7 (br, s ,H) 170 444.43 446.22 1.2 (t? 3H), 2.9 (br s, 6H), 3.25 (m, 2H), 3.6 (brs, 2H), 4.6 (ms 2H), 7.1 (m, 1H), 7.4 (br s, 1H), 7.6 (m, 1H), 7.9 (s, 1H), 8.1 (br s, 1H), 8.2 (s, 1H), 8.3 (m, 1H), 8.6 (d5 1H), 8.7 (d, 1H), 9.1 (s, 1H)5 9.8 (brs, 1H), 10.5 (brs5lH) m 460.2 462.2 (CD3OD) 8.95 (d,1H), 8.86 (d,1H), 8.57 (dt,1H) , 8.46 (d, 1H), 8.17 (d, 1H), 7.93 (t, 1H), 7.62 (br s 1H), 7.33 (d, 1H), 5.14 (m, 1H), 4.42 (q, 2H), 4.26 (ms 1H)S 3.75 (dd, 1H), 3.36 (s, 3H)? 2.81 (s5 3H), 1.42 (d, 3H), 1.30 (t, 3H) ppm 172 485 487 (CD3OD) 1.45-U2 ( m, 3H), 1.9 (m, lH), 2.1 (m, 2H), 2.32 (m, lH), 3.5-3.3 (m, 5H), 3_7 (m, 4H), 3.99 (bsslH), 4.4 (q , 2H), 4.57(bd,lH), 7.58(d,lH),7.8(t,lH), 8.03(s,lH0,8.32(d,lH),8.42(m,2H), 8.75(d,lH) , 8.88(s,lH) 9'l(s,lH). 173 484 486 (CD3OD) L15(t,3H), L4(t,3H), 3.02(8,2^1),3.6(111,2 ^, 3.68 (m, 2HX 3.95 (s, 2H), 4.4 (m, 2H), 4.61 (s, 2H), 7.8 (m, 2H), 8.08 (s, lH), 8.48 (m, 3H), 8.78 (d,lH), 8.9(d,lH),9.17(s,lH). 174 503.2 505.2 (CDCI3) 8.94 (d, 1H)S 8.87 (d, 1H), 8.15 (d, 1H), 8.11 (d , 2H), 7.95 (ddd5 1H), 7.90 (s, 1H)? 7.70 (d, 1H), 7.42 (dd, 1H), 4.76 (s, 2H), 4.46 (q, 2H), 3.82 (t, 4H) ), 3.64 (t, 4H), 3.40 (s, 6H)S 1.45 (t, 3H) 175 593.4 595.3 10.85 (s5 1H); 8.84 (s, 1H); 8.72 (s, 1H); 8.58 (d, 1H 8.52 (s, 1H); 8.30 (d5 1H); 8.08 (s, 1H); 7.92 (d, aH); 7.44 (d, 2H); 7.34 (dd, 2H); 7.24 (t, 1H); 6.05-4.9 (br. s); 5.21 (dqs 1H); 4.78 (d, 2H); 4.31 (q? 2H); 3.58 (d, 2H); 3.52 (176 543.5 545.3 11.76 (s, 1H); 9.59 ( s, 1H); 8.89 (d, 1H);

O:\9O\90896.DOC -88- 1334416 化合物編號I- M-l (obs) M+l (obs) 'HNMR 8.78(s, 1H); 8.65 (s, 1H); 8.40 (s, 1H); 8.05 (d, 1H); 7.9-6.2 (br. s, 2H); 4.87 (d5 2H); 4.32 (qs 2H); 3.96 (dd, 2H); 3.68 (dds 2H); 3.58 (m, 4H);3.20 (m, 2H); 2.94 (d,3H); 1.98 (m, 2H); 1.88 177 542.5 544.3 1U2 (s，1H); 10.84 (s，1H); 9.08 (s， 1H);8.87 (d, 1H); 8.66 (s, 1H); 8.41 (s, 1H); 8.01 (s, 1H); 7.96 (d, 1H);7.58 (s, lH);6.3-4.6 (br. s, 6H); 4.82 (d, 2H); 3.96 (dd, 2H); 3.58(m, 6H); 3.26 (m, 2H); 3.15 (m5 2H); 2.84 (d, 3H); 1.96 ( 178 470.4 472.3 9.05 (d, 2H); 8.54 (s, 1H); 7.89 (s, 1H); 8.01 (s, 1H); 7.78 (d, 1H); 7.55 (t, 1H); 7.05 (d, 1H); 5,5-4.2 (br. s, 1H); 4.33 (q, 2H); 3.50 (dd, 2H); 3.36 (dd, 2H); 3.12 (s, 3H); 2.85 (s, 3H);1.33 (t, 3H). 179 415.4 417.3 (CD3OD) 9.54 (d5 1H), 9.21 (m, 1H)S 9.15 (s，1H)，8.97 (d，1H), 8.92 (d，1H)， 8.83 (d，1H)，8.28 (dd，1H)，8.20 (d，1H), 7.69 (m, 1H), 4.62 (s, 2H)S 4.48 (q, 2H), 3.00 (s，6H), 1.44 (t，3H) ppm 180 414.4 416.3 (CD3OD) 9.54 (d, 1H), 9.22 (m, 1H), 9.05 (s，1H)，8.97 (d，1H)，8.93 (d，1H)， 8.79 (d, 1H), 8.28 (dd5 1H), 8.17 (d, 1H), 7.62 (m，1H)，4.59 (s，2H)，3.39 (q，2H)， 2.99 (s, 6H), 1.25 (t, 3H) ppm 181 513 515 (CD3OD): 9.14(d, 1H), 9.06 (d, 1H), 8.85(t，1H)，8.67 (t，1H)，8.46 (d，1H)， 8.37 (d，1H) 8.11 (m，1H)，7.97(d，1H)， 7.55 (m，1H)，4.07 (brs，2H)，3.88(t，4H)， 3.71 (brs, 2H)S 3.48(t, 4H), 3.36(q, 2H), 1.24(t，3H) 182 477.4 479.37 0.9 (d，6H)，1.3 (t, 3H)，2.1 (m，1H), 2.9 (s，6H)，3.75 (d，2H)，4.3 (q，2H)，4.6 (s， 2H)，6.6 (dt，1H)，6.7 (d，1H)，7.7 (s， 1H), 7.8 (d, 1H), 7.95 (s, 1H), 8.010.2 (br s，1H) (s，1H)， 183 476.42 478.41 0.9 (d，6H)，1.1 (t，3H)，2.1 (m，1H)，2.9 (s，6H)，3.2 (m，2H)，3.8 (d，2H)，4.6 (s， 2H)，6.6 (dt，1H)，6.7 (d，1H)，7.3 (br s， 1H)，7.7 (s，1H)，7.8 (d，1H)，7.95 (s， 1H), 8.0 (s, 1H), 10.2 (brs, 1H) 184 514 516 -O:\9O\90896.DOC -88- 1334416 Compound No. I-Ml (obs) M+l (obs) 'HNMR 8.78(s, 1H); 8.65 (s, 1H); 8.40 (s, 1H); 8.05 (d, 1H); 7.9-6.2 (br. s, 2H); 4.87 (d5 2H); 4.32 (qs 2H); 3.96 (dd, 2H); 3.68 (dds 2H); 3.58 (m, 4H); 3.20 (m, 2H); 2.94 (d, 3H); 1.98 (m, 2H); 1.88 177 542.5 544.3 1U2 (s, 1H); 10.84 (s, 1H); 9.08 (s, 1H); 8.87 (d, 1H) 8.66 (s, 1H); 8.41 (s, 1H); 8.01 (s, 1H); 7.96 (d, 1H); 7.58 (s, lH); 6.3-4.6 (br. s, 6H); 4.82 ( d, 2H); 3.96 (dd, 2H); 3.58 (m, 6H); 3.26 (m, 2H); 3.15 (m5 2H); 2.84 (d, 3H); 1.96 ( 178 470.4 472.3 9.05 (d, 2H) 8.54 (s, 1H); 7.89 (s, 1H); 8.01 (s, 1H); 7.78 (d, 1H); 7.55 (t, 1H); 7.05 (d, 1H); 5,5-4.2 (br s, 1H); 4.33 (q, 2H); 3.50 (dd, 2H); 3.36 (dd, 2H); 3.12 (s, 3H); 2.85 (s, 3H); 1.33 (t, 3H). 179 415.4 417.3 (CD3OD) 9.54 (d5 1H), 9.21 (m, 1H)S 9.15 (s, 1H), 8.97 (d, 1H), 8.92 (d, 1H), 8.83 (d, 1H), 8.28 (dd, 1H) ), 8.20 (d, 1H), 7.69 (m, 1H), 4.62 (s, 2H)S 4.48 (q, 2H), 3.00 (s, 6H), 1.44 (t, 3H) ppm 180 414.4 416.3 (CD3OD) 9.54 (d, 1H), 9.22 (m, 1H), 9.05 (s, 1H), 8.97 (d, 1H), 8.93 (d, 1H), 8.79 (d, 1H), 8.28 (dd5 1H), 8.17 (d , 1H), 7.62 (m,1H), 4.59 (s,2H), 3.39 (q,2H), 2.99 (s, 6H), 1.25 (t, 3H) ppm 181 513 515 (CD3OD): 9.14(d, 1H), 9.06 (d, 1H), 8.85(t,1H), 8.67 (t,1H), 8.46 (d,1H), 8.37 (d,1H) 8.11 (m,1H),7.97(d,1H) , 7.55 (m,1H),4.07 (brs,2H),3.88(t,4H), 3.71 (brs, 2H)S 3.48(t, 4H), 3.36(q, 2H), 1.24(t,3H) 182 477.4 479.37 0.9 (d,6H),1.3 (t, 3H),2.1 (m,1H), 2.9 (s,6H),3.75 (d,2H),4.3 (q,2H),4.6 (s, 2H) , 6.6 (dt, 1H), 6.7 (d, 1H), 7.7 (s, 1H), 7.8 (d, 1H), 7.95 (s, 1H), 8.010.2 (br s, 1H) (s, 1H) , 183 476.42 478.41 0.9 (d,6H),1.1 (t,3H),2.1 (m,1H),2.9 (s,6H),3.2 (m,2H),3.8 (d,2H),4.6 (s, 2H), 6.6 (dt, 1H), 6.7 (d, 1H), 7.3 (br s, 1H), 7.7 (s, 1H), 7.8 (d, 1H), 7.95 (s, 1H), 8.0 (s, 1H), 10.2 (brs, 1H) 184 514 516 -

O:\90\90896.DOC -89- 1334416 化合物編號I- M-l (obs) M+l (obs) 'HNMR 185 470.4 472.2 (CD3OD) 1.25(ts3H) 1.78(d,3H) 3.30(ms2H) 3.35(q,2H) 3.50(m,2H) 3.93 (m，4H)4.73(q，lH) 7.72(t，lH) 7.45(d，lH) 8.01(s,lH) 8.27(t,lH) 8.35(m,2H) 8.52(dslH) 8.91(d,lH) 9.18(s,lH) 186 498.4 500.3 (CD3OD) l_16(m，3H) 1.26(m，6H) 1.80(d53H) 2.82(t52H) 3.20 (d,lH) 3.35(q,2H)3.72(d,lH) 3.91(m,lH) 4.04(m,lH) 4.68(q,lH) 7.65(t?lH) 7.71(d,lH) 8.01(s,lH)8.22(t3lH) 8.35(m,2H) 8.49(d,lH) 8.89(d,lH) 9.18(s51H) 187 499.5 501.3 (CD3OD) 1.16(m,3H) 1.29(ds3H) 1.41(t，3H) 1.79(d，3H)2.82(t，2H) 3.20(d，lH) 3.74(d，lH) 3.92(m，lH) 4.04(m，lH) 4.43(q，2H) 4.69(q，lH) 7.70(d，lH)7.87(t,lH) 8.11(s，lH) 8.35(d，lH) 8.46(m，2H) 8.75(d，lH) 8.92(d，lH)9.34(s，lH) 188 486 488 (CD3OD): 8.91(m, 1H), 8.65 (ms 1H), 8.47(m，1H)，8.31 (m，2H)，8.29 (m，1H)， 7.96 (m5 1H) 7,73 (m5 1H), 7.19(m; 1H), 4_08 (m，2H)，3.90(m，2H)，3.72 (m，4H)， 3.66(m，4H)，3.37(m，2H)，1.24(t, 3H) 189 487 489 (CD3OD): 8.89(d, 1H), 8.69 (d, 1H), 8.61(d3 1H), 8.41 (t, 1H)S 8.32 (d5 1H), 8.20 (dds 1H) 7.95 (d, 1H), 7.78(t, 1H), 7.10 (d, 1H), 4.42(q, 2H), 4.09 (m? 2H), 3.86(m, 2H), 3.70 (m, 4H), 3.33(m, 4H), 1.24(t, 3H) 190 388.38 390.19 1.2 (t, 3H)5 3.3 (m, 2H), 3.5 (s, 3H), 6.6 (dd, 1H), 6.7 (d, 1H)S 7.6 (t, 1H), 7.8 (ds 1H), 7.95 (br s, 1H), 8.0 (s, 1H), 8.6 (s, 1H)? 9.05 (d, 2H) 191 359.3 361.2 - 192 446.4 448.3 - O:\90\90896.DOC -90- 1334416 化合物編號I- M-l (obs) M+l (obs) 'HNMR 193 474.2 476.4 (CD30D) 9.14 (s，1H)，9.08 (d，2H)，8,91 (s，1H)，8.39 (d，1H)，8.14 (s，1H)，7.78 (s，1H)，7.55 (dd，1H)，4.72 (s，2H)，4.48 (q，2H)，3.81(t，2H)，3‘56 (t，2 H)，3.46 (qs 2H)3 3.41 (s, 3H), 1.44 (t, 3H), 1.43 (t，3H) 194 486.1 488.1 (CDC13) 12.31 (br s, 1H), 8.95 (s, 1H)S 8.93 (d, 2H), 8.58 (s, 1H)S 8.05 (s, 1H), 8.01 (d, 1H), 7.50 (d5 1H), 7,24 (dd5 1H), 4.46 (q，2H)，3.78 (m, 2H)，3.72 (s，2H)， 2.78 (d, 2H)S 1.91 (dd, 2H), 1.41 (t, 3H)S 1.17 (d, 6H) 195 - - 11.5 (br sJH), 9.19 (br s, 1H), 8.97 (s, 1H)，8·88 (d，1H)，8.45 (m，1H)，8.40 (s， 1H)，7.98 (d，1H)，7.77 (d，1H)，7.60 (d， 1H), 4.57 (s, 2H)5 4.47 (br d, 2H)S 4.32 (q，2H)，3.90 (br m，4H)，3.32 (br s，4H)， 2.80 (d，6H)，1.34 197 460.2 462.2 (CD3OD &amp;CDCI3)： 8.98 (d, 2H), 8.85 (d, 1H), 8.60 (d, 1H), 8.16 (dds 1H), 7.86 (d, 1H), 7.67 (d, 1H), 7.40 (dd5 1H)? 4.37 (q, 2H), 3.81 (s5 2H), 3.60 (t, 2H), 3.37 (s, 3H), 2.74 (t, 2H), 2.38 (s, 3H), 1.41 (t, 3H) 198 459.3 461.2 (CD3OD): 8.95 (d, 2H), 8.83 (s, 1H), 8.54 (s, 1H), 8.15 (d, 1H), 7.82 (s, 1H)S 7.65 (d; 1H), 7,39 (dd, 1H), 3.79 (s, 2H), 3.59 (t, 2H), 3.36 (q, 2H), 3.35 (s, 3H), 2.72 (t, 2H), 2.36 (s, 3H), 1.24 (t, 3H) 199 488 490 - 200 487 489 - 201 488 490 - 202 487 489 - 203 489 491 9.06(ms 4H)S 8.50 (d, 1H), 7.98(ds 1H), 7.54 (t, 1H)3 4.79(t, 2H), 4.3 l(q, 2H), 4.01 (m, 2H), 3.79 (m, 2H)5 3.67 (m, 2H), 3.56(m5 2H), 3.25(m,2H) 1.33(t, 3H) 204 488 490 (CD3OD): 9.02(m, 4H), 8.75 (s, 1H), O:\90\90896.DOC •91 - 1334416 化合物編號I- M-l (obs) M+l (obs) 'HNMR 7.97(d，1H)，7.52 (m，1H)，4.88(m，2H)， 3.75-3.73(m，10H)，3.35(m，2H)，1.25(t， 3H) 205 400.1 402.1 1.31(t，3H) 2.70(s，3H) 4.32(q，2H) 7.55(t，lH)8.00(s，lH) 8,09(d，lH)8.14(t，lH) 8.39(s，lH) 8.44(d，lH) 8.70(d，lH) 8.81(d，lH) 9.19(s,lH) 206 458.1 460 (CD3OD) 9.41 (d, 2H), 8.92 (m5 1H), 8.80 (d, 1HX 8.48 (m, 2H), 8.10 (br s5 1H), 7.84 (m, 1H), 4.76 (s, 2H with water peak), 4.42 (qs 2H), 4.11 (br m, 2H), 3.95 (nr m, 2H), 3.71 (br m, 2H), 3.45 (br m, 2H), 1.42 (t, 3H) ppm. 207 457.2 459.1 (CD3OD) 9.33 (ss 2H), 8.89 (d, 1H)} 8.53 (d, 1H), 8.44 (d, 1H), 8.20 (m, 1H), 8.04 (d，1H)，7.63 (m，1H)，4.76 (s，2H，with water peak), 4.12 (br m, 2H)? 3.94 (br m, 2H)，3.71 (br m，2H)，3‘44 (br m，2H)， 3.39(q52H)s 1.25 (t, 3H)ppm 208 391 393 - 209 441.1 443 (CD3OD) 1.43(t，3H)4.50(s，2H) 4.89(s，2H) 7.55(t，lH) 8.10(d，lH)8.20(s，lH) 8.87(d，lH) 9.01(s，lH) 9.10(d，2H) 9.30(s，lH) 210 472.4 474.2 (CD3OD) 9.25 (s, 1H), 9.02 (d, 2H), 8.87 (d, 1H), 8.65 (d, 1H)5 8.18 (ss 1H)S 8.08 (d5 1H), 7.54 (dd, 1H), 4.88 (s, 2H), 4.49 (q，2H)，4.27 (br s，1H)，3.68 (m，4H)， 3.40 (s，3H)，2.32 (m，2H)，1.45 (t，3H) 211 471.2 473.1 (CD3OD) 9.16 (s, 1H), 8.98 (d, 2H), 8.76 (d, 1H), 8.48 (d5 1H), 8.05 (s, 1H), 7.91 (d, 1H), 7.50 (dd5 1H), 4.81 (s3 2H), 4.27 (br s，1H)，3.69 (m，4H)，3.40 (s，3H), 3.38 (q, 2H), 2.32 (m, 2H), 1.26 (t, 3H) 212 485.2 487.3 (CD3OD) 9.16 (s, 1H), 9.03 (d, 2H)S 8.87 (ss 1H)S 8.50 (d5 1H), 8.14 (s, 1H)S 7.92 (d, 1H), 7.54 (dd, 1H), 4.75 (s, 2H), 4.49 (qs 2H), 4.06 (s5 2H), 3.74 (br s5 4H), 3.06 (s，3H), 1.45 (t，3H) 213 484.2 486.2 (CD3OD) 9.16 (s, 1H), 9.01 (d, 2H), 8.78 O:\9O\90896.DOC -92- 1334416 化合物編號I- M-l (obs) M+l (obs) 'HNMR (s，1H)，8.52 (d，1H)，8.07 (s，1H)，7.96 (d, 1H), 7.52 (dds 1H), 4.77 (s, 2H)? 4.07 (s, 2H), 3.75 (br s, 4H), 3.38 (q, 2H), 3.06 (s，3H)，1.26 (ts 3H) 214 350.1 12.28 (br. s, 1H); 11.77 (br. s, 1H); 9.73 (s, 1H); 9.08 (d, 2H); 8.49 (d, 1H); 8.37 (m, 1H); 8.08 (d, 1H); 7.94(m, 1H); 7.59 (t, 1H); 4.32 (q, 2H); 2.30 (s, 3H); 1.32 (t, 3H). 215 502.4 504.1 (CD3OD) 9.17 (s5 1H), 9.02 (d, 2H), 8.85 (s, 1H), 8.48 (d, 1H), 8.15 (s, 1H), 7.90 (d, 1H)S 7.53 (dd, 1H), 4.81 (d, 1H), 4.77 (d, 1H), 4.48 (q, 2H), 4.18 (br s, 2H), 3.75 (m, 4H), 3.47 (s, 6H), 1.45 (ts 3H) 216 347.2 349.1 12.28 (br. s, 1H); 10.22 (br. s, 1H); 9.53 (s, 1H); 9.08 (d, 2H); 8.41 (d, 1H); 8.29 (ms 1H); 7.98 (d, 1H); 7.83 (m, 1H); 7.57 (t, 1H); 7.22 (m, 1H); 3.26 (dq, 2H); 2.31 (s, 3H); 1.15 (t,3H). 217 501.4 503.1 (CD3OD) 9.15 (s, 1H), 9.03 (d, 2H), 8.85 (s, 1H), 8.43 (d, 1H)S 8.10 (s, 1H), 7.83 (d, 1H), 7.53 (dd, 1H), 4.78 (d, 1H), 4.74 (ds 1H), 4.18 (br s5 2H), 3.74 (m, 4H), 3.47 (s, 6H), 3.38 (q, 2H), 1.26 (t, 3H) 218 456 458 (CD3OD) L24(t,3H), 3.38(ms2H), 3.57(bs，4H)，3.99(bs，4H)，4.63(s，2H)， 7.68(m，lH)，7.73(m，lH)， 8.02(s,lH),8.24(t,lH), 8.48(m,lH), 8.49(d，lH)，8.9(d，lH)，9.13(s，lH)· 219 - - 12.25 (s, 1H); 11.75 (s, 1H); 9.61 (d, 1H); 9.07 (d, 2H); 8.45 (s, 1H); 8.11 (s, 1H); 8.02 (d, 1H); 7.59 (t, 1H); 4.31 (q5 2H); 2.38 (s, 3H); 2.29 (s, 3H); 1.32 (t5 3H). 220 502.3 504.2 (CD3OD) 9.10 (d, 1H), 9.05 (d, 2H), 8.91 (d，1H)，8.32 (dd，1H)，8·11 (d，1H)， 7.69 (d，1H)，7.55 (dd，1H)，4.73 (d，1H)， 4.69 (d, 1H), 4.49 (q, 2K), 4.17 (br ss 2H), 3.70 (m, 4H), 3.46 (s, 6H), 1.44 (t, 3H) 221 501.3 503.2 (CD3OD) 9.09 (s, 1H), 9.05 (d, 2H), 8.86 (s, 1H), 8.29 (d, 1H), 8.09 (s, 1H), 7.67 O:\90\9O896.DOC -93- 1334416 化合物編號I- M-l (obs) M+l (obs) *HNMR (d，1H)，7.54 (dd，1H)，4.72 (d，1H)，4.67 (d, 1H), 4.17 (br s, 2H), 3.71 (m, 4H), 3.47 (s, 6H), 3.39 (q, 2H), 1.26 (t, 3H) 222 - 559 (CDC13) 12.29 (br s, 1H), 8.94 (s, 1H), 8.94 (d, 2H)5 8.60 (s, 1H), 8.04 (s, 1H), 8.02 (d, 1H), 7.50 (d, 1H), 7.25 (dd, 1H), 4.46 (q, 2H), 3.75 (s, 2H), 3.50 (m, 4H), 2.51 (m, 4H)S 1.47 (s, 9H)S 1.41 (t, 3H) 223 513.2 515.14 1.1 (d, 6H), 1.3 (t5 3H), 3.5 (m, 4H), 3.7 (br s, 2H), 4.3 (q, 2H), 4.5 (br s, 2H), 4.65 (m, 1H)S 7.5 (t, 1H), 7.7 (d, 1H), 8.0 (d, 1H), 8.3 (dd, 1H), 8.5 (d, 1H), 9.0 (ds 2H), 9.05 (d, 1H) 224 457.207 459.207 (CD3OD) 9.54 (s, 1H), 9.28 (s, 1H)3 9.22 (d, 1H), 8.97 (d, 1H), 8.93 (d, 1H), 8.85 (br s, 1H), 8.27 (t, 1H), 8.20 (br s, 1H), 7.71 (d, 1H), 4.63 (s, 2H), 4.48 (q, 2H), 4.05 (br s, 4H), 3.44 (br m, 4H), 1.44 (t, 3H) ppm 225 472.2 474.49 (CD3OD) 9.0(ds 1H)S 8.95(m, 1H), 8.6(s, 1H)，8.5(s，1H)，8.4(s3 lH)，8.3(s，1H)， 7.9(s，1H)，7.55(m，1H)，4.5 (s，2H)， 3.9(s, 2H),3.4(q, 2H), 3.0(ss 6H), 1.3 (t, 3H), 226 562.3 564.2 (CD3OD) 9.0(d, 1H), 8.9(m, 1H), 8.6(s, 1H), 8.5(s; 1H), 8.3(s, 1H), 8.25(s, 1H)，7.9(S，lH)，7.55(m，1H)，7.3-7.4(m, 5H)} 5.2(s, 2H), 4.5(s5 2H)3 4.0(s, 2H), 3.4(q, 2H), 3.0(s, 6H), 1.3(t, 3H) 227 389 391 - 228 457.3 459.1 - 229 456.3 458.1 - 230 433.3 435.1 - 231 487 489 (CD3OD) 9.30 (s, 2H), 9.04 (d, 2H), 8.89 (d, lH),8.11(d, 1H), 7.54 (t, 1H), 4.46 (q, 2H), 4.02 (m, 2H), 3.59 (m, 2H), 2.89 (m, 2H), 1.44 (t, 2H), 1.13 (t, 3H) ppm. O:\90\90896.DOC -94- 1334416 化合物编號I- M-l (obs) M+l (obs) 'H nmr 232 456.3 458.3 (CD3OD) 9.22 (s, 1H), 9.05 (d, 2H), 8.92 (s，1H)，8.78 (d，1H)，8.Π (s，1H)，8.08 (d，1H)，7.54 (dd，1H)，4.42 (s，2H)，3.，52 (m，4H)，3.39 (q，4H), 3.28 (m，4H)，1.26 (t，3H) 233 - 459.1 (CD3OD) 9.22 (s, 1H), 9.06 (d, 2H), 8.96 (s, 1H), 8.77 (d, 1H), 8.22 (s, 1H), 8.07 (d，1H)，7.56 (dd，1H)，4.49 (q，2H)，4.42 (s，2H)，3.，52 (m，4H), 3.29 (m，4H)， 1.45 (t, 3H) 234 - 537 (CD3OD) 9.22 (s, 1H), 9.04(d, 2H), 8.90 (s, 1H), 8.54(d, 1H), 8.16 (s, 1H), 7.99 (d，1H)，7.54 (dd，1H)，4.78 (s，2H)，4.49 (q, 2H), 3.69 &amp;3.63 (m, 8H), 3.00 (s, 3H)，1.45(t，3H) 235 534.2 536.1 (CD3OD) 9.20 (s, 1H), 9.02(d, 2H), 8.82 (s，1H)，8.52(d，1H)，8.09 (s，1H)，7.98 (d, 1H)} 7.52 (dd, 1H), 4.78 (s, 2H), 3.69 &amp;3.62 (m, 8H), 3.39 (q, 2H), 3.00 (s, 3H), 1.25 (t, 3H) 236 496.4 498.3 (CD3OD) 9.28 (s? 1H), 9.06 (br s, 2H), 8.96 (s, 1H), 8.85 (br s, 1H), 8.24 (s, 1H), 8.15 (br s, 1H), 7.56 (br s, 1H), 4.49 (q, 2H), 4.42 (s5 2H), 3.73(br s, 4H), 3.35 (br s, 4H), 3.01 (br s, 1H), 1.45 (t, 3H), 1.20 (brs, 2H), 1.00 (brs2H) 237 496.4 498.3 (CDCI3) 11.82 (br s, 1H)? 8.88 (s, 1H), 8.71 (br s, 2H), 8.48 (s, 1H), 7.89 (d, 1H)? 7.79 (s, 1H), 7.42 (d, 1H), 7.05 (br s, 1H), 3.71 (s, 2H), 3.46 (q;2H), 2.70 &amp; 2.55 (ms 8H), 1.28 (t, 3H), 0.45-0.41 (m, 4H) 238 447.2 449 12.35 (s, 1H); 9.07 (d, 2H); 8.82 (s, 1H); 8.41 (d, 1H); S.13 (s, 1Η);·.7.95 (d5 1H); 7.57 (t, 1H); 6.7-5.2 (br. s, 4H); 4.38 (s, 2H); 4.32 (q, 2H); 3.92 (br. d, 4H); 3.32 (br. (1,4Η); 1.33 (t, 3H). 239 490.1 492.2 (CD3OD) 9.21 (s, 1H)S 9.05 (d, 2H), 8.92 (s，1H)，8.54 (d，1H)，8.17 (s，1H)，7.97 (d, 1H), 7.55 (dd, 1H)S 4.78 (s, 2H), 4.49 (q，2H)，4.01 (br dd，2H)，3.74 (br d， 2H), 3.43 (br dd, 2H), 3.27 (br d, 2H),O:\90\90896.DOC -89- 1334416 Compound No. I- Ml (obs) M+l (obs) 'HNMR 185 470.4 472.2 (CD3OD) 1.25(ts3H) 1.78(d,3H) 3.30(ms2H) 3.35( q,2H) 3.50(m,2H) 3.93 (m,4H)4.73(q,lH) 7.72(t,lH) 7.45(d,lH) 8.01(s,lH) 8.27(t,lH) 8.35(m, 2H) 8.52(dslH) 8.91(d,lH) 9.18(s,lH) 186 498.4 500.3 (CD3OD) l_16(m,3H) 1.26(m,6H) 1.80(d53H) 2.82(t52H) 3.20 (d,lH) 3.35(q,2H)3.72(d,lH) 3.91(m,lH) 4.04(m,lH) 4.68(q,lH) 7.65(t?lH) 7.71(d,lH) 8.01(s,lH)8.22( t3lH) 8.35(m,2H) 8.49(d,lH) 8.89(d,lH) 9.18(s51H) 187 499.5 501.3 (CD3OD) 1.16(m,3H) 1.29(ds3H) 1.41(t,3H) 1.79(d, 3H)2.82(t,2H) 3.20(d,lH) 3.74(d,lH) 3.92(m,lH) 4.04(m,lH) 4.43(q,2H) 4.69(q,lH) 7.70(d,lH) 7.87(t,lH) 8.11(s,lH) 8.35(d,lH) 8.46(m,2H) 8.75(d,lH) 8.92(d,lH)9.34(s,lH) 188 486 488 (CD3OD): 8.91 (m, 1H), 8.65 (ms 1H), 8.47 (m, 1H), 8.31 (m, 2H), 8.29 (m, 1H), 7.96 (m5 1H) 7,73 (m5 1H), 7.19 (m; 1H), 4_08 (m, 2H), 3.90 (m, 2H), 3.72 (m, 4H), 3.66 (m, 4H), 3.37 (m, 2H), 1.24 (t, 3H) 189 487 489 (CD3OD): 8.89 (d, 1H), 8.69 (d, 1H), 8.61 (d3 1H), 8.41 (t, 1H)S 8.32 (d5 1H), 8.20 (dds 1H) 7.95 (d, 1H), 7.78 (t, 1H), 7.10 (d, 1H), 4.42(q, 2H), 4.09 (m? 2H), 3.86(m, 2H), 3.70 (m, 4H), 3.33(m, 4H), 1.24( t, 3H) 190 388.38 390.19 1.2 (t, 3H)5 3.3 (m, 2H), 3.5 (s, 3H), 6.6 (dd, 1H), 6.7 (d, 1H)S 7.6 (t, 1H), 7.8 (ds 1H), 7.95 (br s, 1H), 8.0 (s, 1H), 8.6 (s, 1H)? 9.05 (d, 2H) 191 359.3 361.2 - 192 446.4 448.3 - O:\90\90896.DOC - 90- 1334416 Compound No. I- Ml (obs) M+l (obs) 'HNMR 193 474.2 476.4 (CD30D) 9.14 (s,1H), 9.08 (d,2H),8,91 (s,1H),8.39 ( d, 1H), 8.14 (s, 1H), 7.78 (s, 1H), 7.55 (dd, 1H), 4.72 (s, 2H), 4.48 (q, 2H), 3.81 (t, 2H), 3'56 (t,2 H), 3.46 (qs 2H)3 3.41 (s, 3H), 1.44 (t, 3H), 1.43 (t,3H) 194 486.1 488.1 (CDC13) 12.31 (br s, 1H), 8.95 (s , 1H)S 8.93 (d, 2H), 8.58 (s, 1H)S 8.05 (s, 1H), 8.01 (d, 1H), 7.50 (d5 1H), 7,24 (dd5 1H), 4.46 (q, 2H), 3.78 (m, 2H), 3.72 (s, 2H), 2.78 (d, 2H)S 1.91 (dd, 2H), 1.41 (t, 3H)S 1.17 (d, 6H) 195 - - 11.5 (br sJH), 9.19 (br s, 1H), 8.97 (s, 1H), 8.88 (d, 1H), 8.45 (m, 1H), 8.40 (s, 1H), 7.98 (d, 1H), 7.77 (d, 1H), 7.60 (d, 1H), 4.57 (s, 2H)5 4.47 (br d, 2H)S 4.32 (q, 2H), 3.90 (br m, 4H), 3.32 (br s, 4H), 2.80 (d, 6H), 1.34 197 460.2 462.2 (CD3OD &amp; CDCI3): 8.98 (d, 2H), 8.85 (d, 1H), 8.60 (d, 1H), 8.16 (dds 1H), 7.86 (d, 1H), 7.67 (d, 1H), 7.40 (dd5 1H)? 4.37 (q, 2H), 3.81 (s5 2H), 3.60 (t, 2H), 3.37 (s, 3H), 2.74 (t , 2H), 2.38 (s, 3H), 1.41 (t, 3H) 198 459.3 461.2 (CD3OD): 8.95 (d, 2H), 8.83 (s, 1H), 8.54 (s, 1H), 8.15 (d, 1H) ), 7.82 (s, 1H)S 7.65 (d; 1H), 7,39 (dd, 1H), 3.79 (s, 2H), 3.59 (t, 2H), 3.36 (q, 2H), 3.35 (s, 3H), 2.72 (t, 2H), 2.36 (s, 3H), 1.24 (t, 3H) 199 488 490 - 200 487 489 - 201 488 490 - 202 487 489 - 203 489 491 9.06 (ms 4H)S 8.50 ( d, 1H), 7.98(ds 1H), 7.54 (t, 1H)3 4.79(t, 2H), 4.3 l(q, 2H), 4.01 (m, 2H), 3.79 (m, 2H)5 3.67 (m , 2H), 3.56(m5 2H), 3.25(m,2H) 1.33(t, 3H) 204 488 490 (CD3OD): 9.02(m, 4H), 8.75 (s, 1H), O:\90 \90896.DOC •91 - 1334416 Compound No. I- Ml (obs) M+l (obs) 'HNMR 7.97(d,1H),7.52 (m,1H),4.88(m,2H), 3.75-3.73(m , 10H), 3.35 (m, 2H), 1.25 (t, 3H) 205 400.1 402.1 1.31 (t, 3H) 2.70 (s, 3H) 4.32 (q, 2H) 7.55 (t, lH) 8.00 (s, lH) 8,09(d,lH)8.14(t,lH) 8.39(s,lH) 8.44(d,lH) 8.70(d,lH) 8.81(d,lH) 9.19(s,lH) 206 458.1 460 (CD3OD) 9.41 (d, 2H), 8.92 (m5 1H), 8.80 (d, 1HX 8.48 (m, 2H), 8.10 (br s5 1H), 7.84 (m, 1H), 4.76 (s, 2H with water peak), 4.42 (qs 2H), 4.11 (br m, 2H), 3.95 (nr m, 2H), 3.71 (br m, 2H), 3.45 (br m, 2H), 1.42 (t, 3H) ppm. 207 457.2 459.1 (CD3OD ) 9.33 (ss 2H), 8.89 (d, 1H)} 8.53 (d, 1H), 8.44 (d, 1H), 8.20 (m, 1H), 8.04 (d, 1H), 7.63 (m, 1H), 4.76 (s, 2H, with water peak), 4.12 (br m, 2H)? 3.94 (br m, 2H), 3.71 (br m, 2H), 3'44 (br m, 2H), 3.39 (q52H)s 1.25 (t, 3H)ppm 208 391 393 - 209 441.1 443 (CD3OD) 1.43(t,3H)4.50(s,2H) 4.89(s,2H) 7.55(t,lH) 8.10(d,lH)8.20(s, lH) 8.87(d,lH) 9.01(s,lH) 9.10(d,2H) 9.3 0(s,lH) 210 472.4 474.2 (CD3OD) 9.25 (s, 1H), 9.02 (d, 2H), 8.87 (d, 1H), 8.65 (d, 1H)5 8.18 (ss 1H)S 8.08 (d5 1H ), 7.54 (dd, 1H), 4.88 (s, 2H), 4.49 (q, 2H), 4.27 (br s, 1H), 3.68 (m, 4H), 3.40 (s, 3H), 2.32 (m, 2H) ), 1.45 (t, 3H) 211 471.2 473.1 (CD3OD) 9.16 (s, 1H), 8.98 (d, 2H), 8.76 (d, 1H), 8.48 (d5 1H), 8.05 (s, 1H), 7.91 ( d, 1H), 7.50 (dd5 1H), 4.81 (s3 2H), 4.27 (br s, 1H), 3.69 (m, 4H), 3.40 (s, 3H), 3.38 (q, 2H), 2.32 (m, 2H), 1.26 (t, 3H) 212 485.2 487.3 (CD3OD) 9.16 (s, 1H), 9.03 (d, 2H)S 8.87 (ss 1H)S 8.50 (d5 1H), 8.14 (s, 1H)S 7.92 ( d, 1H), 7.54 (dd, 1H), 4.75 (s, 2H), 4.49 (qs 2H), 4.06 (s5 2H), 3.74 (br s5 4H), 3.06 (s, 3H), 1.45 (t, 3H ) 213 484.2 486.2 (CD3OD) 9.16 (s, 1H), 9.01 (d, 2H), 8.78 O:\9O\90896.DOC -92- 1334416 Compound No. I- Ml (obs) M+l (obs) 'HNMR (s, 1H), 8.52 (d, 1H), 8.07 (s, 1H), 7.96 (d, 1H), 7.52 (dds 1H), 4.77 (s, 2H)? 4.07 (s, 2H), 3.75 (br s, 4H), 3.38 (q, 2H), 3.06 (s, 3H), 1.26 (ts 3H) 214 350.1 12.28 (br. s, 1H); 11.77 (br. s, 1H); 9.73 (s, 1H); 9.08 (d, 2H); 8.49 (d, 1H); 8.37 (m, 1H); 8.08 (d, 1H) 7.94(m, 1H); 7.59 (t, 1H); 4.32 (q, 2H); 2.30 (s, 3H); 1.32 (t, 3H). 215 502.4 504.1 (CD3OD) 9.17 (s5 1H), 9.02 (d, 2H), 8.85 (s, 1H), 8.48 (d, 1H), 8.15 (s, 1H), 7.90 (d, 1H)S 7.53 (dd, 1H), 4.81 (d, 1H), 4.77 ( d, 1H), 4.48 (q, 2H), 4.18 (br s, 2H), 3.75 (m, 4H), 3.47 (s, 6H), 1.45 (ts 3H) 216 347.2 349.1 12.28 (br. s, 1H) 10.22 (br. s, 1H); 9.53 (s, 1H); 9.08 (d, 2H); 8.41 (d, 1H); 8.29 (ms 1H); 7.98 (d, 1H); 7.83 (m, 1H) 7.57 (t, 1H); 7.22 (m, 1H); 3.26 (dq, 2H); 2.31 (s, 3H); 1.15 (t, 3H). 217 501.4 503.1 (CD3OD) 9.15 (s, 1H), 9.03 (d, 2H), 8.85 (s, 1H), 8.43 (d, 1H)S 8.10 (s, 1H), 7.83 (d, 1H), 7.53 (dd, 1H), 4.78 (d, 1H), 4.74 ( Ds 1H), 4.18 (br s5 2H), 3.74 (m, 4H), 3.47 (s, 6H), 3.38 (q, 2H), 1.26 (t, 3H) 218 456 458 (CD3OD) L24(t,3H) , 3.38 (ms2H), 3.57 (bs, 4H), 3.99 (bs, 4H), 4.63 (s, 2H), 7.68 (m, lH), 7.73 (m, lH), 8.02 (s, lH), 8.24 ( t,lH), 8.48(m,lH), 8.49(d,lH) 8.9(d,lH),9.13(s,lH)· 219 - - 12.25 (s, 1H); 11.75 (s, 1H); 9.61 (d, 1H); 9.07 (d, 2H); 8.45 (s, 1H) 8.11 (s, 1H); 8.02 (d, 1H); 7.59 (t, 1H); 4.31 (q5 2H); 2.38 (s, 3H); 2.29 (s, 3H); 1.32 (t5 3H). 220 502.3 504.2 (CD3OD) 9.10 (d, 1H), 9.05 (d, 2H), 8.91 (d, 1H), 8.32 (dd, 1H), 8·11 (d, 1H), 7.69 (d, 1H), 7.55 (dd,1H), 4.73 (d,1H), 4.69 (d, 1H), 4.49 (q, 2K), 4.17 (br ss 2H), 3.70 (m, 4H), 3.46 (s, 6H), 1.44 ( t, 3H) 221 501.3 503.2 (CD3OD) 9.09 (s, 1H), 9.05 (d, 2H), 8.86 (s, 1H), 8.29 (d, 1H), 8.09 (s, 1H), 7.67 O:\90 \9O896.DOC -93- 1334416 Compound No. I- Ml (obs) M+l (obs) *HNMR (d,1H), 7.54 (dd,1H), 4.72 (d,1H), 4.67 (d, 1H) , 4.17 (br s, 2H), 3.71 (m, 4H), 3.47 (s, 6H), 3.39 (q, 2H), 1.26 (t, 3H) 222 - 559 (CDC13) 12.29 (br s, 1H), 8.94 (s, 1H), 8.94 (d, 2H)5 8.60 (s, 1H), 8.04 (s, 1H), 8.02 (d, 1H), 7.50 (d, 1H), 7.25 (dd, 1H), 4.46 (q, 2H), 3.75 (s, 2H), 3.50 (m, 4H), 2.51 (m, 4H)S 1.47 (s, 9H)S 1.41 (t, 3H) 223 513.2 515.14 1.1 (d, 6H), 1.3 (t5 3H), 3.5 (m, 4H), 3.7 (br s, 2H), 4.3 (q, 2H), 4.5 (br s, 2H), 4.65 (m, 1H)S 7.5 (t, 1H), 7.7 (d, 1H), 8.0 (d, 1H), 8.3 (dd, 1H), 8.5 (d, 1H), 9.0 (ds 2H), 9.05 (d, 1H) 224 457.207 459.207 (CD3OD) 9.54 (s, 1H), 9.28 (s, 1H)3 9.22 (d, 1H), 8.97 (d, 1H), 8.93 (d, 1H), 8.85 (br s, 1H), 8.27 (t, 1H), 8.20 (br s, 1H), 7.71 (d, 1H), 4.63 (s, 2H), 4.48 (q, 2H), 4.05 (br s, 4H), 3.44 (br m, 4H), 1.44 (t, 3H) Ppm 225 472.2 474.49 (CD3OD) 9.0 (ds 1H)S 8.95 (m, 1H), 8.6 (s, 1H), 8.5 (s, 1H), 8.4 (s3 lH), 8.3 (s, 1H), 7.9 (s , 1H), 7.55 (m, 1H), 4.5 (s, 2H), 3.9 (s, 2H), 3.4 (q, 2H), 3.0 (ss 6H), 1.3 (t, 3H), 226 562.3 564.2 (CD3OD 9.0(d, 1H), 8.9(m, 1H), 8.6(s, 1H), 8.5(s; 1H), 8.3(s, 1H), 8.25(s, 1H), 7.9(S,lH), 7.55(m,1H),7.3-7.4(m, 5H)} 5.2(s, 2H), 4.5(s5 2H)3 4.0(s, 2H), 3.4(q, 2H), 3.0(s, 6H), 1.3(t, 3H) 227 389 391 - 228 457.3 459.1 - 229 456.3 458.1 - 230 433.3 435.1 - 231 487 489 (CD3OD) 9.30 (s, 2H), 9.04 (d, 2H), 8.89 (d, lH), 8.11 (d, 1H), 7.54 (t, 1H), 4. 46 (q, 2H), 4.02 (m, 2H), 3.59 (m, 2H), 2.89 (m, 2H), 1.44 (t, 2H), 1.13 (t, 3H) ppm. O:\90\90896. DOC -94- 1334416 Compound No. I- Ml (obs) M+l (obs) 'H nmr 232 456.3 458.3 (CD3OD) 9.22 (s, 1H), 9.05 (d, 2H), 8.92 (s, 1H), 8.78 (d,1H),8.Π (s,1H),8.08 (d,1H),7.54 (dd,1H),4.42 (s,2H),3.,52 (m,4H),3.39 (q , 4H), 3.28 (m, 4H), 1.26 (t, 3H) 233 - 459.1 (CD3OD) 9.22 (s, 1H), 9.06 (d, 2H), 8.96 (s, 1H), 8.77 (d, 1H) , 8.22 (s, 1H), 8.07 (d, 1H), 7.56 (dd, 1H), 4.49 (q, 2H), 4.42 (s, 2H), 3., 52 (m, 4H), 3.29 (m, 4H), 1.45 (t, 3H) 234 - 537 (CD3OD) 9.22 (s, 1H), 9.04(d, 2H), 8.90 (s, 1H), 8.54(d, 1H), 8.16 (s, 1H), 7.99 (d,1H), 7.54 (dd,1H), 4.78 (s,2H), 4.49 (q, 2H), 3.69 &amp;3.63 (m, 8H), 3.00 (s, 3H), 1.45 (t, 3H) ) 235 534.2 536.1 (CD3OD) 9.20 (s, 1H), 9.02 (d, 2H), 8.82 (s, 1H), 8.52 (d, 1H), 8.09 (s, 1H), 7.98 (d, 1H)} 7.52 (dd, 1H), 4.78 (s, 2H), 3.69 &amp;3.62 (m, 8H), 3.39 (q, 2H), 3.00 (s, 3H), 1.25 (t, 3H) 236 496.4 49 8.3 (CD3OD) 9.28 (s? 1H), 9.06 (br s, 2H), 8.96 (s, 1H), 8.85 (br s, 1H), 8.24 (s, 1H), 8.15 (br s, 1H), 7.56 (br s, 1H), 4.49 (q, 2H), 4.42 (s5 2H), 3.73 (br s, 4H), 3.35 (br s, 4H), 3.01 (br s, 1H), 1.45 (t, 3H) , 1.20 (brs, 2H), 1.00 (brs2H) 237 496.4 498.3 (CDCI3) 11.82 (br s, 1H)? 8.88 (s, 1H), 8.71 (br s, 2H), 8.48 (s, 1H), 7.89 ( d, 1H)? 7.79 (s, 1H), 7.42 (d, 1H), 7.05 (br s, 1H), 3.71 (s, 2H), 3.46 (q; 2H), 2.70 &amp; 2.55 (ms 8H), 1.28 (t, 3H), 0.45-0.41 (m, 4H) 238 447.2 449 12.35 (s, 1H); 9.07 (d, 2H); 8.82 (s, 1H); 8.41 (d, 1H); S.13 ( s, 1Η);·..7.95 (d5 1H); 7.57 (t, 1H); 6.7-5.2 (br. s, 4H); 4.38 (s, 2H); 4.32 (q, 2H); 3.92 (br. d , 4H); 3.32 (br. (1,4Η); 1.33 (t, 3H). 239 490.1 492.2 (CD3OD) 9.21 (s, 1H)S 9.05 (d, 2H), 8.92 (s, 1H), 8.54 ( d,1H), 8.17 (s,1H), 7.97 (d, 1H), 7.55 (dd, 1H)S 4.78 (s, 2H), 4.49 (q, 2H), 4.01 (br dd, 2H), 3.74 ( Br d, 2H), 3.43 (br dd, 2H), 3.27 (br d, 2H),

O:\90\90896.DOC -95- 1334416 化合物編號I- M-l (obs) M+l (obs) lHNMR 1.45 (t, 3H) 240 471.3 473 (CD3OD) 9.28 (s, 1H), 9.05 (br s5 2H)5 8.96 (s, 1H), 8.89 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.55 (br s, 1H), 4.49 (q, 2H), 4.39 (s5 2H), 3.64-3.13 (m, 8H)S 3.00 (s, 3H), 1.45 (t, 3H) 241 - 531.01 1.3 (t, 3H), 1.55 (d, 3H), 3.3 (br s, 4H), 3.9 (br s, 4H), 4.0 (q, 1H), 4.35 (q, 2H), 4.6 (s，2H), 7.6 (dd, 1H)，7.8 (d，1H)，8.0 (s，1H)，8.4 (d，1H)，8.42 (s，1H)，8.7 (s， 1H)，8.8 (d，1H)，9·15 (s，1H)，11 …2 (br S，1H) 242 486.2 488.1 (CD3OD) 9.33 (s, 2H), 8.92 (d, 1H), 8.79 (d，1H)，8,47 (m，2H)，8.09 (d，1H)，7.84 (m, 1H), 4.42 (q5 2H), 4.05 (m, 2H)S 3.67 (m, 2H), 3.39 (ms 2H, underneath solvent peak), 3.00 (m, 2H), 1.42 (t, 3H), 1.28 (ds 6H) ppm 243 488.2 490.05 1.3 (t5 3H), 3.2 (m, 2H), 3.5 (m, 2H), 3.7 (m, 2H), 3.9 (m, 2H), 4.0 (m, 2H), 4.3 (q, 2H), 4.8 (m, 2H), 7.6 (7, 1H), 8.1 (d, 1H)，8.2 (br s, 1H), 8.6 (d，1H)，8.65 (d， 1H)5 8.8 (d, 1H)S 9.05 (d, 2H), 11.6 (br s, 1H), 12.7 (br s, 1H) 244 457.21 459.09 1.35 (t，3H)，2.8 (br s，3H)，3.2 (m，2H)， 3.4 (m，2H)，3.55 (m，2H)，4.3 (m，2H)， 4.35 (q，2H)，7.6 (t，1H)，8_1 (d，1H)，8.3 (br s，1H)，8.55 (d，1H)，8.6 (d，1H)，8.7 (d，lH)，9.05(d，2H)，11.2(brs，1H)， 12.4 (brs, 1H) 245 529.2 531.1 (CD3OD) 9.08 (d, 1H), 9.01 (d, 2H), 8_82 (d，1H)，8,30 (d，1H)，8.04 (d，1H)， 7.68 (d，1H)，7.51 (dd，1H)，4·63 (s，2H)， 4.47 (q, 2H), 4.22 (s, 2H), 3.91 (br s, 4H), 3.49 (br ss 4H)S 3.43 (s, 3H), 1.44 (t, 3H) 246 555.3 557.1 (CD3OD) 9.23 (s, 1H), 9.04 (d, 2H)5 8.90 (s, 1H), 8.56 (d, 1H), 8.17 (s, 1H), 8.00 (ds 1H)5 7.55 (dd, 1H), 4.77 (s, 2H), 4.49 (q, 2H), 4.12-3.84 (m, 6H)S 3.57 (br s, 4H),3.48 (brs, lH)52.18(m, 2H), 1.97 (m5 2H), 1.45 (t, 3H) O:\9O\90896.DOC -96- 1334416 1化合物編號ι- M-l (obs) M+l (obs) *HNMR 247 485.1 487 (CD3OD) 9.34 (s, 2H), 8.93 (d, 1H)S 8.80 (ds 1H)S 8.48 (m, 2H)S 8.10 (d, 1H), 7.85 (t5 1H), 4.88 (s, 2H)S 4.44 (q, 2H)S 4.21 (s, 2H), 3.86 (m5 2H), 3.79 (m, 2H), 3.09 (s, 3H), 1.42 (t, 3H) ppm. 248 458.15 460.02 1.23(UH) 3.17(m,4H) 3.65(m,4H) 4.34(q，2H) 4.77(s，2H)7.57(t，lH) 8.11(s，lH) 8.61(s，lH) 9.06(d，2H) 9.39(s，2H) 9.87(br s，2H) 249 472.3 474 (CD3OD) 9.17 (s, 1H), 9.04 (d, 2H), 8.92 (s, 1H), 8.45 (d, 1H), 8.15 (s, 1H), 7.87 (d, 1H)S 7.55 (dd, 1H)S 4.68 (s, 2H), 4.69 (q, 2H), 4.11 (dds 1H)S 4.02-3.95 (m, 2H), 3.57 (m, 2H), 3.03 (dd? 1H), 1.44 (ts 3H), 1.26 (d,3H) 250 499.2 501.3 (CD3OD) 9.25 (s5 1H)5 9.06 (d, 2H), 8.97 (s，1H)，8.84 (d，1H)，8.23 (s，1H)，8.12 (d，1H)，7.56 (dd，1H)，4.49 (q，2H)，4.37 (s，2H)，3.65-3.12 (m，9H)，1.46-1.43 (m， 9H) 251 514.9 517 (CD3OD) 9.27 (s, 1H), 9.05 (d, 2H)? 8.95 (s，1H)，8.86 (d，1H)，8.25 (s，1H)，8.16 (d，1H)，7.56 (dd，1H)，4_49 (q，2H)，4.46 (s，2H)，3.81-3.50 (m，12 H)，3.44 (s， 3H), 1.45 (t, 3H) 252 527.2 529 (CD3OD) 9.06 (s, 1H), 8.97(d, 2H), 8.76 (s，1H)，8.28 (d，1H)，8.00 (s，1H)，7.69 (d，1H)，7.49 (dd，1H)，4.65 (s，2H)，4.45 (q, 2H), 3.99 (br s, 4H), 3.49 (br s, 4H), 2.99 (hept, 1H), 1.44 (t, 3H), 1.14 (d, 6H) 253 502 504 (CD3OD) 9.08 (d, 2H), 8.73 (s5 1H), 8.51 (s, 1H), 8.38 (dd, 1H), 8.07 (d, 1H),7.92 (m, 1H)S 7.77 (d, 1H)S 7.64 (m, 1H), 4.67 (s, 2H)S 4.48 (q5 2H), 4.01(s, 2H), 3.65 (m5 4H)，3.06 (m，2H), 1.43 (t，2H)，1.13 (ts 3H) ppm. O:\90\90896.DOC 97- 1334416 化合物编號I- M-l (obs) M+l (obs) *HNMR 254 454.17 456.02 14.52 (s, 1H); 9.22 (s, 2H); 9.05 (d, 2H); 8.56 (ds 1H); 8.04 (d, 1H); 7.74 (ss 1H); 7.62 (s, 1H); 7.55 (t, 1H); 6.8-5-6 (br. s); 5.79 (s, 2H); 4.33 (q, 2H); 2.62 (s, 3H); 1.33 (t，3H). 255 530.17 532.03 1.1 (d, 6H), 1.35 (t, 3H), 2.3 (s, 6H), 3.5 (ms 2H), 3.6 (m3 2H), 3.9 (s, 2H), 4.3 (q, 2H), 4,6 (s5 2H)S 4.65 (m, 1H), 7.7 (d, 1H), 7.9 (s, 1H), 8.0 (dt, 1H), 8.3 (s5 1H), 8.4 (dds 1H), 8.8 (d, 1H)3 8.85 (m, 1H), 9.1 (s5 1H) 256 486.23 488.05 1.3 (d, 6H), 1.35 (t, 3H), 3.1 (m, 2H), 3.5 (m, 1H), 3.6 (m, 4H), 4.3 (q, 2H), 4.8 (m, 2H); 7.6 (t, 1H), 7.9 (s, 1H), 8.5 (s, 1H), 8.9 (s, 2H)3 9.05 (d; 1H)? 10.5 (br s, 1H) 257 499.2 501.1 (CD3OD) 9.34 (s, 2H), 8.93 (m, 1H), 8.81 (d, 1H), 8.49 (m, 2H), 8.11 (d, 1H), 7.85 (t，1H)，4.87 (s, 2H)，4.42 (q, 2H)， 4.11 (br s5 2H)? 3.87 (br m; 4H), 3.71 (m, 3H)，1.48 (d，6H)，1.42 (t，3H) ppm. 258 571.3 573.1 (CDCI3) 12.75 (br s, 1H), 12.29 (s, 1H), 8.94 (d，2H)，8.92 (s，1H)，8.60 (s，1H)， 8.05 (s，1H)，8.04 (d，1H)，7.59 (d，1H)， 7.25 (dd, 1H)? 4.46 (q? 2H); 4.23 (br s, 1H)，3·86 (d，1H)，3.80 (d，1H)，3.65 (d， 1H)，3.19 (ddd，1H)，2.86 (d，1H)，2.66 (d，1H) 259 - 473 (CD3OD) 9.24 (s，1H)，9.04 (d，2H)，8.94 (s, 1H), 8.81 (d; 1H), 8.22 (s, 1H), 8.11 (d, 1H)S 7.55 (dd, 1H), 4.49 (q, 2H), 4.42 (s, 2H)? 3.77-2.89 (m, 7H), 1.45 (t, 3H), 1.41 (d, 3H) 260 485.3 487.3 (CD3OD) 9.24 (s, 1H), 9.06 (ds 2H), 8.96 (s, 1H)S 8.83 (d, 1H), 8.23 (s, 1H), 8.11 (d，1H)，7.56 (dd，1H)，4.49 (q，2H)，4.39 (s, 2H), 3.76 (m5 2H)S 3.40 (d, 2H), 2.80 (d, 2H), 1.45 (t, 3H), 1.40 (d, 6H) 261 485.2 487 (CD3OD) 9.23 (s; 1H)S 9.06 (d, 2H), 8.97 (s? 1H), 8.82 (d? \H), 8.24 (s, 1H), 8.13 (d，1H)，7.56 (dd，1H), 4.74 (d，2H), 4.49 (q，2H)，4.25 (d，1H)，3.80-2.92 (m，6H)， O:\90\90896.DOC -98- 1334416 化合物编號I- M-l (obs) M+l (obs) *HNMR 1.45 (t,3H), 1.36 (d, 6H) 262 513.2 515 (CD3OD) 9.10 (s, 1H), 9.02 (d, 2H), 8.85 (s，1H), 8.31 (d, 1H)，8.06 (s，1H), 7.68 (d，1H)，7.52 (dd，1H)，4.62 (s，2H)，4.46 (q, 2H)S 3.92-3.16 (m, 8 H), 2.48 (q5 2H)5 1.86 (m, 2H)S 1.44 (t, 3H), 1.14 (t5 3 H) 263 - 557.3 (CD3OD) 9.11 (s，1H)，9.03 (d，2H)，8.85 (s, 1H), 8.32 (ds 1H), 8.07 (s, 1H), 7.69 (d, 1H)S 7.52 (dd, 1H)? 4.63 (s, 2H), 4.47 (q, 2H), 3.99-3.79 (m5 8 H), 3.50-3.45 (m，5H)，2.15 (m，2H), 1.44 (t，3H) 264 - 501.1 (CD3OD) 9.10 (s, 1H), 9.03 (d, 2H), 8.85 (s, 1H), 8.62 (d, 1H)S 8.08 (s, 1H), 7.94 (d, 1H), 7.52 (dd, 1H), 4.46 (q5 2H), 4.12 (s, 2H), 3.46-3.01 (m, 10H),1.80 (m, 2H), 1.43 (t, 3H), 1.04 (t, 3H) 265 - 531.1 (CD3OD) 9.21 (s, 1H), 8.96 (d, 2H)S 8.82 (ss 1H), 8.59 (ds 1H), 8.12 (s, 1H), 8.06 (d, 1H), 7.48 (dd5 1H), 4.75 (s, 2H), 4.42 (qs 2H), 4.12 (q, 2H), 3.83 (br s, 4H), 3.47 (br s? 4H), 1.38 (t5 3H), 1.23 (t3 3H) 266 543.2 545 (CD3OD) 9.33 (s, 1H)S 8.99 (d, 2H), 8.83 (s, 1H)S 8.79 (br s, 1H), 8.18 (s, 1H), 7.54 (br s, 1H), 4.93 (m, 1H), 4.89 (s, 2H), 4.49 (q, 2H), 3.90 (br s, 4H), 3.57 (br s, 4H), 1.45 (t, 3H), 1.29 (d, 6H) 267 516 518 - 268 557.3 559.2 (CD3OD) 9.08 (s, 1H), 8.969 (d, 2H), 8.78 (s, 1H)S 8.29 (d, 1H)? 8.01 (s, 1H), 7.67 (d, 1H), 7.49 (dd, 1H), 4.62 (ss 2H), 4.45 (q, 2H), 3.93 (d, 2H)3 3.85 (br s, 4H), 3.46 (br s, 4H), 1.96 (m, 1H)S 1.43 (t, 3 H), 0.98 (d5 6 H) 269 553.3 555.1 (CD3OD) 9.15 (s3 1H), 9.05 (d, 2H); 8.91 (s, 1H), 8.39 (d, 1H), 8.14 (s, 1H), 7.79 (d, 1H), 7.55 (dd, 1H), 4.71 (q, 2H)? 4.68 (s，2H)，4.49 (q，2H)，3.88 (br s，4H)， 3.49 (br s，4H)，1.82 (t，3H)，1,44 (t，3 H) 270 557.3 559.2 (CD3OD) 9]1 (s，1H)，9.03 (d，2H)，8.84 (s, 1H), 8.31 (d? 1H), 8.05 (ss 1H), 7.68 (d, 1H), 7.52 (dd, 1H), 4.63 (s, 2H), 4.46 O:\9O\90S96.DOC -99- 1334416 化合物編號I- M-l (obs) M+l (obs) 'hnmr (q, 2H), 3.96 (br s, 4H), 3.52 (br s, 2H), 3.44 (br s5 2H), 2.71( t, 2H), 2.65 (ts 2H), 1.43 (t,3H) 271 573.2 575.2 (CD3OD) 9.12 (s3 1H), 9.05 (d, 2H), 8.86 (s，1H)，8.32 (d，1H)，8.07 (s，1H)，7.68 (d，1H)，7*53 (dd，1H)，4.63 (s，2H)，4.46 (q，2H)，4,37 (s，2H)，4.21 (s，2H)，3·98 (br s，4H)，3.52 (br s，2H)，3.47 (br s， 2H), 1.44 (t,3H) 272 500.23 502.05 1.21(m，9H) 3.17(s，lH) 3.61(m，8H) 4.32(q，2H) 4.65(s，2H)7.56(t，lH) 8.10(s，lH) 8.58(s，lH)9.07(d，2H) 9.30(s，2H) 273 476 478 9.29(s, 2H), 8.66 (s, 1H), 8.02(s, 1H)S 7.95 (m, 2H), 7.59 (m, 1H), 4.76(s, 2H), 4.30 (m, 2H),3.94-3.68(m, 4H), 3.50-3.17(m,4H), 1.30(ts 3H) 274 417.1 419 9.1(s, 2H), 9.0(s, 2H), 8.4(s, 1H), 7.8(s, 1H), 7.5(t, lH),4.1-4,2(q, 2H), 3.7(s, 2H)S 2.3(s, 6H), 1.3(t, 3H). 275 466 468 - 276 445.1 447 1.33(t,3H) 2.06(m,lH) 2.26(m,lH) 3.88(ms4H) 4.33(qs2H)5.85(m?lH) 6_97(d，lH) 7.55(t，lH) 7.91(s，lH) 8.08(d,lH) 8.52(m,2H)9.05(d,2H) 12.44(br s,lH) 277 475.1 477 1.3 (t, 3H), 2.3 (s, 6H), 3.35 (m, 4H), 3.9 (m, 4H), 4.3 (q, 2H), 4.6 (s, 2H)? 7.7 (d, 1H), 7.9 (s, 1H), 8.0 (dt, 1H), 8.3 (s, 1H), 8,35 (dd, 1H), 8.75 (d, 1H)5 8.8 (br s5 1H), 9.1((1,111),10.4 (brs, 1H) 278 502.1 504 1.3 (t, 3H), 3.2 (s, 3H), 3.4 (brs, 4H)S 3.7 (br ss 4H), 3.8 (br s, 2H), 4.3 (q, 2H), 4.8 (br s, 2H), 7.55 (t, 1H), 8.0 (d, 1H), 8.5 (ds 1H), 9.0 (s, 2H), 9.05 (d, 2H), 11.8 (br ss 1H), 12.6 (brs, 1H) 279 525.2 527 - 280 567.2 569 (CD3OD) 9.11 (s, 1H), 9.03 (d, 2H), 8.83 (s, 1H), 8.33 (d, 1H), 8.06 (s, 1H), 7.68 (d, 1H), 7.52 (dd, 1H), 4.63 (s, 2H), 4.46 O:\90\90896.DOC •100- 化合物編號I- M-1 (obs) M+1 (obs) 'hnmr (q, 2H), 3.94 (ms 4H), 3.59 (q, 2H), 3.47 (m5 4H), 1.44 (t,3H) 281 458.15 459.98 9.11 (br. s, 2H); 9.09 (s5 1H); 8.82 (d, 1H); 8.78(br. s, 1H); 8.64 (d, 1H); 8.28 (s, 1H); 8.10 (dd5 1H); 7.88 (s, 1H); 7.52 (dds 1H); 5.38 (m, 1H); 5.5-4.2 (br. s5 4H); 4.32 (q, 2H); 3.45 (m, 1H); 3.37 (m, lH);3.12(m, 2H);2.05 (M, 1 282 514.2 516 10.05 (m, 1H);9.24 (m, lH);9.15(d, 2H); 8.82 (d, 1H); 8.67 (d, 1H); 8.31 (s, 1H); 8.12 (m, 1H); 7.90 (s, 1H); 7.53 (m, 1H); 5.52 (m3 1H); 4.32 (q, 2H); 3.78 (m, lH);3.55-2.88 (m, 4H); 2.12 (m, 1H); 2.02 (m, 1H); 1.88 (m, 1H); 1.33 (t 283 519.15 521.02 1.3 (t,3H), 2.35 (s, 12H),2.8(s, 3H)，.3.0-3.7 (br s，10H)，4.3 (q，2H)，4.7 (br s, 2H), 7.6 (m, 1H), 7.9 (s, 1H)S 7.95 (m，2H)，8.65 (m，1H), 9.0 (s，2H) 290 487.1 489 - 291 - 490 292 482.1 484 - 293 483 484.9 - 294 460.11 461.96 1.15 (t, 3H), 2.3 (s5 9H), 3.25 (m5 2H), 3.5 (m，4H)，3.8 (m，4H)，7.5 (br s，1H)， 7.6 (ms 1H), 7.95 (m, 1H)S 8.0 (s, 1H), 8.1 (m, 1H), 8.2 (m, 1H), 8.4 (d, 1H), 8.6 (s，1H)，8.7 (d，1H)，10.3 (br s，1H) 295 - - (CD3OD) 9.13 (d，1H)，9.05 (d，2H)， 8.92 (d，1H)，8.37 (m，1H)，8_13 (d，1H)， 7.75 (dt，1H)，7.55 (t，1H)，4.70 (s，2H)， 4.49 (qs 2H), 3.62 (m, 4H), 2.47 (m, 4H), 1.44 (t, 3H) ppm 1334416 實例27 促旋酶ATP酶化驗 藉由將經由丙酮酸鹽激酶/乳酸去氫酶之ADP製備連結至 O:\9O\90896.DOC • 101 - 1334416 NADH的氧化作用測量DNA促旋酶的ATP水解活性。先前已 描述此方法（Tamura和 Gellert，1990，J. Biol. Chem.，265， 21342)。 ATP酶化驗於 30°C 在包含 100 mM TRIS pH 7.6，1.5 mM MgCl2，150 mM KC1之缓衝溶液中進行。連結系統包含（最 後濃度）2·5 mM磷酸烯醇丙酮酸，200 μΜ菸鹼醯胺腺嘌呤 二核嘗酸（NADH)，1 mM DTT，30 pg/毫升丙酮酸鹽激酶， 和10 pg/毫升乳酸去氫酶。加入40奈莫耳酵素（來自金黃色 葡萄球菌之374 kDa Gyr A2B2亞單元）及抑制劑之DMSO 溶液至4%之最後濃度和使反應混合物於30 °C培養10分 鐘。然後以加入ATP至0.9 mM的最後濃度開始反應及測量 10分鐘於340奈米NADH消失之速率。從速率對濃度分佈圖 測定Ki值。 發現本發明化合物抑制促旋酶。在某些具體實施例中， 在上述化驗中本發明化合物以小於50 nM的Ki值抑制促旋 酶。 實例28O:\90\90896.DOC -95- 1334416 Compound No. I- Ml (obs) M+l (obs) lHNMR 1.45 (t, 3H) 240 471.3 473 (CD3OD) 9.28 (s, 1H), 9.05 (br s5 2H)5 8.96 (s, 1H), 8.89 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.55 (br s, 1H), 4.49 (q, 2H), 4.39 (s5 2H ), 3.64-3.13 (m, 8H)S 3.00 (s, 3H), 1.45 (t, 3H) 241 - 531.01 1.3 (t, 3H), 1.55 (d, 3H), 3.3 (br s, 4H), 3.9 (br s, 4H), 4.0 (q, 1H), 4.35 (q, 2H), 4.6 (s, 2H), 7.6 (dd, 1H), 7.8 (d, 1H), 8.0 (s, 1H), 8.4 (d, 1H), 8.42 (s, 1H), 8.7 (s, 1H), 8.8 (d, 1H), 9·15 (s, 1H), 11 ... 2 (br S, 1H) 242 486.2 488.1 (CD3OD ) 9.33 (s, 2H), 8.92 (d, 1H), 8.79 (d, 1H), 8, 47 (m, 2H), 8.09 (d, 1H), 7.84 (m, 1H), 4.42 (q5 2H) , 4.05 (m, 2H)S 3.67 (m, 2H), 3.39 (ms 2H, underneath solvent peak), 3.00 (m, 2H), 1.42 (t, 3H), 1.28 (ds 6H) ppm 243 488.2 490.05 1.3 ( T5 3H), 3.2 (m, 2H), 3.5 (m, 2H), 3.7 (m, 2H), 3.9 (m, 2H), 4.0 (m, 2H), 4.3 (q, 2H), 4.8 (m, 2H), 7.6 (7, 1H), 8.1 (d, 1H), 8.2 (br s, 1H), 8.6 (d, 1H), 8.65 (d, 1H)5 8.8 (d, 1H)S 9 .05 (d, 2H), 11.6 (br s, 1H), 12.7 (br s, 1H) 244 457.21 459.09 1.35 (t,3H),2.8 (br s,3H),3.2 (m,2H), 3.4 ( m, 2H), 3.55 (m, 2H), 4.3 (m, 2H), 4.35 (q, 2H), 7.6 (t, 1H), 8_1 (d, 1H), 8.3 (br s, 1H), 8.55 ( d,1H),8.6 (d,1H),8.7 (d,lH),9.05(d,2H),11.2(brs,1H), 12.4 (brs, 1H) 245 529.2 531.1 (CD3OD) 9.08 (d, 1H ), 9.01 (d, 2H), 8_82 (d, 1H), 8, 30 (d, 1H), 8.04 (d, 1H), 7.68 (d, 1H), 7.51 (dd, 1H), 4·63 ( s,2H), 4.47 (q, 2H), 4.22 (s, 2H), 3.91 (br s, 4H), 3.49 (br ss 4H)S 3.43 (s, 3H), 1.44 (t, 3H) 246 555.3 557.1 (CD3OD) 9.23 (s, 1H), 9.04 (d, 2H)5 8.90 (s, 1H), 8.56 (d, 1H), 8.17 (s, 1H), 8.00 (ds 1H)5 7.55 (dd, 1H) , 4.77 (s, 2H), 4.49 (q, 2H), 4.12-3.84 (m, 6H)S 3.57 (br s, 4H), 3.48 (brs, lH) 52.18(m, 2H), 1.97 (m5 2H) , 1.45 (t, 3H) O:\9O\90896.DOC -96- 1334416 1 Compound Number ι- Ml (obs) M+l (obs) *HNMR 247 485.1 487 (CD3OD) 9.34 (s, 2H), 8.93 (d, 1H)S 8.80 (ds 1H)S 8.48 (m, 2H)S 8.10 (d, 1H), 7.85 (t5 1H), 4.88 (s, 2H)S 4.44 (q, 2H)S 4.21 (s, 2H), 3.86 (m5 2H), 3.79 (m, 2H), 3.09 (s, 3H), 1.42 (t, 3H) ppm. 248 458.15 460.02 1.23(UH) 3.17 (m,4H) 3.65(m,4H) 4.34(q,2H) 4.77(s,2H)7.57(t,lH) 8.11(s,lH) 8.61(s,lH) 9.06(d,2H) 9.39(s ,2H) 9.87(br s,2H) 249 472.3 474 (CD3OD) 9.17 (s, 1H), 9.04 (d, 2H), 8.92 (s, 1H), 8.45 (d, 1H), 8.15 (s, 1H) , 7.87 (d, 1H)S 7.55 (dd, 1H)S 4.68 (s, 2H), 4.69 (q, 2H), 4.11 (dds 1H)S 4.02-3.95 (m, 2H), 3.57 (m, 2H) , 3.03 (dd? 1H), 1.44 (ts 3H), 1.26 (d, 3H) 250 499.2 501.3 (CD3OD) 9.25 (s5 1H)5 9.06 (d, 2H), 8.97 (s, 1H), 8.84 (d, 1H), 8.23 (s, 1H), 8.12 (d, 1H), 7.56 (dd, 1H), 4.49 (q, 2H), 4.37 (s, 2H), 3.65-3.12 (m, 9H), 1.46-1.43 (m, 9H) 251 514.9 517 (CD3OD) 9.27 (s, 1H), 9.05 (d, 2H)? 8.95 (s, 1H), 8.86 (d, 1H), 8.25 (s, 1H), 8.16 (d, 1H), 7.56 (dd, 1H), 4_49 (q, 2H), 4.46 (s, 2H), 3.81-3.50 (m, 12 H), 3.44 (s, 3H), 1.45 (t, 3H) 252 527.2 529 (CD3OD) 9.06 (s, 1H), 8.97(d, 2H), 8.76 (s, 1H), 8.28 (d, 1H), 8.00 (s, 1H) ), 7.69 (d, 1H), 7.49 (dd, 1H), 4.65 (s, 2H), 4.45 (q, 2H), 3.99 (br s, 4H), 3.49 (br s, 4H), 2.99 (hept, 1H), 1.44 (t, 3H), 1.14 (d, 6H) 253 502 504 (CD3OD) 9.08 (d, 2H), 8.73 (s5 1H), 8.51 (s, 1H), 8.38 (dd, 1H), 8.07 (d, 1H), 7.92 (m, 1H)S 7.77 (d, 1H)S 7.64 (m, 1H), 4.67 (s, 2H)S 4.48 (q5 2H), 4.01(s, 2H), 3.65 (m5 4H), 3.06 (m, 2H), 1.43 (t, 2H), 1.13 (ts 3H) ppm. O:\90\90896.DOC 97- 1334416 Compound number I- Ml (obs) M+l (obs) *HNMR 254 454.17 456.02 14.52 (s, 1H); 9.22 (s, 2H); 9.05 (d, 2H); 8.56 (ds 1H); 8.04 (d, 1H); 7.74 (ss 1H); 7.62 (s, 1H 7.55 (t, 1H); 6.8-5-6 (br. s); 5.79 (s, 2H); 4.33 (q, 2H); 2.62 (s, 3H); 1.33 (t, 3H). 255 530.17 532.03 1.1 (d, 6H), 1.35 (t, 3H), 2.3 (s, 6H), 3.5 (ms 2H), 3.6 (m3 2H), 3.9 (s, 2H), 4.3 (q, 2H), 4, 6 (s5 2H)S 4.65 (m, 1H), 7.7 (d, 1H), 7.9 (s, 1H), 8.0 (dt, 1H), 8.3 (s5 1H), 8.4 (dds 1H), 8.8 (d, 1H)3 8.85 (m, 1H), 9.1 (s5 1H) 256 486.23 488.05 1.3 (d, 6H), 1.35 (t, 3H), 3.1 (m, 2H), 3.5 (m, 1H), 3.6 (m, 4H), 4.3 (q, 2H ), 4.8 (m, 2H); 7.6 (t, 1H), 7.9 (s, 1H), 8.5 (s, 1H), 8.9 (s, 2H)3 9.05 (d; 1H)? 10.5 (br s, 1H 257 499.2 501.1 (CD3OD) 9.34 (s, 2H), 8.93 (m, 1H), 8.81 (d, 1H), 8.49 (m, 2H), 8.11 (d, 1H), 7.85 (t, 1H), 4.87 (s, 2H), 4.42 (q, 2H), 4.11 (br s5 2H)? 3.87 (br m; 4H), 3.71 (m, 3H), 1.48 (d, 6H), 1.42 (t, 3H) ppm. 258 571.3 573.1 (CDCI3) 12.75 (br s, 1H), 12.29 (s, 1H), 8.94 (d, 2H), 8.92 (s, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 8.04 (d,1H), 7.59 (d,1H), 7.25 (dd, 1H)? 4.46 (q? 2H); 4.23 (br s, 1H),3·86 (d,1H), 3.80 (d,1H) , 3.65 (d, 1H), 3.19 (ddd, 1H), 2.86 (d, 1H), 2.66 (d, 1H) 259 - 473 (CD3OD) 9.24 (s, 1H), 9.04 (d, 2H), 8.94 ( s, 1H), 8.81 (d; 1H), 8.22 (s, 1H), 8.11 (d, 1H)S 7.55 (dd, 1H), 4.49 (q, 2H), 4.42 (s, 2H)? 3.77-2.89 (m, 7H), 1.45 (t, 3H), 1.41 (d, 3H) 260 485.3 487.3 (CD3OD) 9.24 (s, 1H), 9.06 (ds 2H), 8.96 (s, 1H)S 8.83 (d, 1H ), 8.23 (s, 1H), 8.11 (d, 1H), 7.56 (dd, 1H), 4.49 (q, 2H), 4.39 (s, 2H), 3.76 (m5 2H)S 3.40 (d , 2H), 2.80 (d, 2H), 1.45 (t, 3H), 1.40 (d, 6H) 261 485.2 487 (CD3OD) 9.23 (s; 1H)S 9.06 (d, 2H), 8.97 (s? 1H) , 8.82 (d? \H), 8.24 (s, 1H), 8.13 (d,1H), 7.56 (dd,1H), 4.74 (d,2H), 4.49 (q,2H), 4.25 (d,1H) , 3.80-2.92 (m, 6H), O:\90\90896.DOC -98- 1334416 Compound No. I- Ml (obs) M+l (obs) *HNMR 1.45 (t,3H), 1.36 (d, 6H) 262 513.2 515 (CD3OD) 9.10 (s, 1H), 9.02 (d, 2H), 8.85 (s, 1H), 8.31 (d, 1H), 8.06 (s, 1H), 7.68 (d, 1H), 7.52 (dd,1H), 4.62 (s,2H), 4.46 (q, 2H)S 3.92-3.16 (m, 8 H), 2.48 (q5 2H)5 1.86 (m, 2H)S 1.44 (t, 3H) , 1.14 (t5 3 H) 263 - 557.3 (CD3OD) 9.11 (s, 1H), 9.03 (d, 2H), 8.85 (s, 1H), 8.32 (ds 1H), 8.07 (s, 1H), 7.69 (d , (H, H), 4. 1.44 (t,3H) 264 - 501.1 (CD3OD) 9.10 (s, 1H), 9.03 (d, 2H), 8.85 (s, 1H), 8.62 (d, 1H)S 8.08 (s, 1H), 7.94 (d , 1H), 7.52 (dd, 1H), 4.46 (q5 2H), 4.12 (s, 2H), 3.46-3.01 (m, 10H), 1.80 (m, 2H), 1.43 (t, 3H), 1.0 4 (t, 3H) 265 - 531.1 (CD3OD) 9.21 (s, 1H), 8.96 (d, 2H)S 8.82 (ss 1H), 8.59 (ds 1H), 8.12 (s, 1H), 8.06 (d, 1H ), 7.48 (dd5 1H), 4.75 (s, 2H), 4.42 (qs 2H), 4.12 (q, 2H), 3.83 (br s, 4H), 3.47 (br s? 4H), 1.38 (t5 3H), 1.23 (t3 3H) 266 543.2 545 (CD3OD) 9.33 (s, 1H)S 8.99 (d, 2H), 8.83 (s, 1H)S 8.79 (br s, 1H), 8.18 (s, 1H), 7.54 (br s, 1H), 4.93 (m, 1H), 4.89 (s, 2H), 4.49 (q, 2H), 3.90 (br s, 4H), 3.57 (br s, 4H), 1.45 (t, 3H), 1.29 (d, 6H) 267 516 518 - 268 557.3 559.2 (CD3OD) 9.08 (s, 1H), 8.969 (d, 2H), 8.78 (s, 1H)S 8.29 (d, 1H)? 8.01 (s, 1H), 7.67 (d, 1H), 7.49 (dd, 1H), 4.62 (ss 2H), 4.45 (q, 2H), 3.93 (d, 2H)3 3.85 (br s, 4H), 3.46 (br s, 4H), 1.96 (m, 1H)S 1.43 (t, 3 H), 0.98 (d5 6 H) 269 553.3 555.1 (CD3OD) 9.15 (s3 1H), 9.05 (d, 2H); 8.91 (s, 1H), 8.39 (d , 1H), 8.14 (s, 1H), 7.79 (d, 1H), 7.55 (dd, 1H), 4.71 (q, 2H)? 4.68 (s, 2H), 4.49 (q, 2H), 3.88 (br s ,4H), 3.49 (br s,4H),1.82 (t,3H),1,44 (t,3 H) 270 557.3 559.2 (CD3OD) 9]1 (s,1H),9.03 (d,2H ), 8.84 (s, 1H), 8.31 (d? 1H), 8.05 (ss 1H), 7.68 (d, 1H), 7.52 (dd, 1H), 4.63 (s, 2H), 4.46 O:\9O\90S96 .DOC -99- 1334416 Compound Number I- Ml (obs) M+l (obs) 'hnmr (q, 2H), 3.96 (br s, 4H), 3.52 (br s, 2H), 3.44 (br s5 2H) , 2.71( t, 2H), 2.65 (ts 2H), 1.43 (t, 3H) 271 573.2 575.2 (CD3OD) 9.12 (s3 1H), 9.05 (d, 2H), 8.86 (s, 1H), 8.32 (d, 1H), 8.07 (s, 1H), 7.68 (d, 1H), 7*53 (dd, 1H), 4.63 (s, 2H), 4.46 (q, 2H), 4, 37 (s, 2H), 4.21. (s, 2H), 3·98 (br s, 4H), 3.52 (br s, 2H), 3.47 (br s, 2H), 1.44 (t, 3H) 272 500.23 502.05 1.21 (m, 9H) 3.17 (s , lH) 3.61 (m, 8H) 4.32 (q, 2H) 4.65 (s, 2H) 7.56 (t, lH) 8.10 (s, lH) 8.58 (s, lH) 9.07 (d, 2H) 9.30 (s, 2H) ) 273 476 478 9.29(s, 2H), 8.66 (s, 1H), 8.02(s, 1H)S 7.95 (m, 2H), 7.59 (m, 1H), 4.76(s, 2H), 4.30 (m, 2H), 3.94-3.68 (m, 4H), 3.50-3.17 (m, 4H), 1.30 (ts 3H) 274 417.1 419 9.1 (s, 2H), 9.0 (s, 2H), 8.4 (s, 1H), 7.8(s, 1H), 7.5(t, lH), 4.1-4, 2(q, 2H), 3.7(s, 2H)S 2.3(s, 6H), 1.3(t, 3H). 275 466 468 - 276 445.1 447 1.33 (t,3H) 2.06(m,lH) 2.26(m,lH) 3.88(ms4H) 4.33(qs2H)5.85(m?lH) 6_97(d,lH) 7.55(t,lH) 7.91(s,lH) 8.08 (d,lH) 8.52(m,2H)9.05(d,2H) 12.44(br s,lH) 277 475.1 477 1.3 (t, 3H), 2.3 (s, 6H), 3.35 (m, 4H), 3.9 ( m, 4H), 4.3 (q, 2H), 4.6 (s, 2H)? 7.7 (d, 1H), 7.9 (s, 1H), 8.0 (dt, 1H), 8.3 (s, 1H), 8,35 (dd, 1H), 8.75 (d, 1H)5 8.8 (br s5 1H), 9.1 ((1,111), 10.4 (brs, 1H) 278 502.1 504 1.3 (t, 3H), 3.2 (s, 3H), 3.4 (brs, 4H)S 3.7 (br ss 4H), 3.8 (br s, 2H), 4.3 (q, 2H), 4.8 (br s, 2H), 7.55 (t, 1H), 8.0 (d, 1H), 8.5 (ds 1H), 9.0 (s, 2H), 9.05 (d, 2H), 11.8 (br ss 1H), 12.6 (brs, 1H) 279 525.2 527 - 280 567.2 569 (CD3OD) 9.11 (s, 1H), 9.03 (d, 2H), 8.83 (s, 1H), 8.33 (d, 1H), 8.06 (s, 1H), 7.68 (d, 1H), 7.52 (dd, 1H), 4.63 (s, 2H), 4.46 O:\90\90896.DOC •100- Compound No. I- M-1 (obs) M+1 (obs) 'hnmr (q, 2H), 3.94 (ms 4H), 3.59 (q, 2H), 3.47 ( M5 4H), 1.44 (t,3H) 281 458.15 459.98 9.11 (br. s, 2H); 9.09 (s5 1H); 8.82 (d, 1H); 8.78 (br. s, 1H); 8.64 (d, 1H) ; 8.28 (s, 1H); 8.10 (dd5 1H); 7.88 (s, 1H); 7.52 (dds 1H); 5.38 (m, 1H); 5.5-4.2 (br. s5 4H); 4.32 (q, 2H); 3.45 (m, 1H); 3.37 (m, lH) ; 3.2 (m, 2H); 2.05 (M, 1 282 514.2 516 10.05 (m, 1H); 9.24 (m, lH); 9.15 (d, 2H); 8.82 (d, 1H); 8.67 (d, 1H) 8.31 (s, 1H); 8.12 (m, 1H); 7.90 (s, 1H); 7.53 (m, 1H); 5.52 (m3 1H); 4.32 (q, 2H); 3.78 (m, lH); -2.88 (m, 4H); 2.12 (m, 1H); 2.02 (m, 1H); 1.88 (m, 1H); 1.33 (t 283 519.15 521.02 1.3 (t,3H), 2.35 (s, 12H), 2.8 (s, 3H), .3.0-3.7 (br s, 10H), 4.3 (q, 2H), 4.7 (br s, 2H), 7.6 (m, 1H), 7.9 (s, 1H)S 7.95 (m, 2H), 8.65 (m, 1H), 9.0 (s, 2H) 290 487.1 489 - 291 - 490 292 482.1 484 - 293 483 484.9 - 294 460.11 461.96 1.15 (t, 3H), 2.3 (s5 9H), 3.25 (m5 2H), 3.5 (m, 4H), 3.8 (m, 4H), 7.5 (br s, 1H), 7.6 (ms 1H), 7.95 (m, 1H)S 8.0 (s, 1H), 8.1 (m, 1H) ), 8.2 (m, 1H), 8.4 (d, 1H), 8.6 (s, 1H), 8.7 (d, 1H), 10.3 (br s, 1H) 295 - - (CD3OD) 9.13 (d, 1H), 9.05 (d, 2H), 8.92 (d, 1H), 8.37 (m, 1H), 8_13 (d, 1H), 7.75 (dt, 1H), 7.55 (t, 1H), 4.70 (s, 2H), 4.49 (qs 2H), 3.62 (m, 4H), 2.47 (m, 4H), 1.44 (t, 3H) ppm 1334416 Example 27 Gyrase ATPase assay by going through pyruvate kinase/lactic acid The ADP preparation of hydrogenase is linked to O:\9O\90896.DOC • 101 - 1334416 The oxidation of NADH measures the ATP hydrolysis activity of DNA gyrase. This method has been previously described (Tamura and Gellert, 1990, J. Biol. Chem., 265, 21342). The ATPase assay was carried out at 30 ° C in a buffer solution containing 100 mM TRIS pH 7.6, 1.5 mM MgCl2, 150 mM KCl. The ligation system contains (final concentration) 2·5 mM phosphoenolpyruvate, 200 μM nicotine guanamine adenine dinuclear acid (NADH), 1 mM DTT, 30 pg/ml pyruvate kinase, and 10 pg/ Milliliter of lactate dehydrogenase. 40 Namir enzyme (from the 374 kDa Gyr A2B2 subunit of S. aureus) and the inhibitor's DMSO solution were added to a final concentration of 4% and the reaction mixture was incubated at 30 °C for 10 minutes. The reaction was then started with the addition of ATP to a final concentration of 0.9 mM and the rate at which NADH disappeared at 340 nm was measured for 10 minutes. The Ki value was determined from the rate versus concentration profile. The compounds of the invention were found to inhibit gyrase. In certain embodiments, the compounds of the invention inhibit the gyrase at a Ki value of less than 50 nM in the assay described above. Example 28

Topo IV ATP酶化驗： 將藉由Τορο4酵素之ΑΤΡ到ADP的轉化連結至NADH ▲ NAD+之轉化及以在340 nm之收吸度的改變測量。Topo4與 抑制劑（4%DMSO最終）一起在緩衝液中於30°C培養10分 鐘。反應以ATP開始，及在分子裝置SpectraMAX盤讀計於 3 0°C連續監測速率20分鐘。抑制常數，Ki，從適合緊結合 抑制劑的Morrison式之速率對[抑制劑]的作圖測定。 O:\9O\90896.DOC -102- 1334416 金黃色葡萄球菌Τορο4緩衝液： 100 mM Tris 7.5，2 mM MgCl〗，200 mM Κ ·谷胺酸鹽， 2.5 mM 磷酸烯醇丙酮酸，0.2 mM NADH，1 mM DTT，4.25 pg/毫升線性化DNA，50 pg/毫升BSA，30 pg/毫升丙酮酸 鹽激酶，和10 pg/毫升乳酸鹽去氫酶（LDH)。 大桿腸菌Topo4緩衝液： 100 mM Tris 7.5，6 mM MgCl2，20 mM KCn，2.5 mM 磷 酸烯醇丙酮酸，0_2 mM NADH，10 mM DTT，5.25 pg/毫升 線性化DNA，50 pg/毫升BSA，30 #g/毫升丙酮酸鹽激， 和10 pg/毫升乳酸鹽去氫酶（LDH)。 發現本發明化合物抑制TopoIV。在某些具體實施例中， 在上述化驗中本發明化合物以小於50 nM的Ki值抑制 TopoIV。 實例29 在液態培養基中之敏感性測試 也藉由在液態培養基中之靈敏度測試測試本發明化合物 之抗微生物活性。該等化驗在規定該實務之最近NCCLS文 件的指導範圍内進行：”用於需氧生長的細菌稀釋抗微生物 靈敏度測試之M7-A5方法；核准標準-第五版（2000)”。其他 出版例如''在實驗室醫學中之抗生素&quot;（由V. Lorian，出版 社，威廉和Wilkins編輯，1996)提供實驗室抗生素測試之基 本實務技術。基本上，得自新劃線培養m的金黃色葡萄球 菌之幾個不連續的細菌菌落（3到7)轉移到適當富含流體培 養基例如MHB，若適當補充複雜難養的生物。此生長過夜 O:\90\90896.DOC -103- 1334416 至咼密度接著稀釋1或2千-倍以產生每毫升5χ1〇5*5χ1〇6 CFU之間的培養密度。或者，新揀菌落可在37。〇培養約*到 8個小蚧直到培養物等於或超過〇 5 標準的濁度 (每毫升約1 _5Χ1〇8細胞）且稀釋以產生與上述相同的每毫升Topo IV ATPase assay: The conversion of Τορο4 enzyme to ADP is linked to the conversion of NADH ▲ NAD+ and measured by the change in absorbance at 340 nm. Topo4 was incubated with the inhibitor (4% DMSO final) in buffer at 30 ° C for 10 minutes. The reaction was started with ATP and continuously monitored at a temperature of 30 ° C for 20 minutes on a molecular device SpectraMAX disk. The inhibition constant, Ki, was determined from the Morrison-type rate of the tight binding inhibitor to the [inhibitor] plot. O:\9O\90896.DOC -102- 1334416 Staphylococcus aureus Τορο4 buffer: 100 mM Tris 7.5, 2 mM MgCl, 200 mM Κ · glutamate, 2.5 mM phosphoenolpyruvate, 0.2 mM NADH , 1 mM DTT, 4.25 pg/ml linearized DNA, 50 pg/ml BSA, 30 pg/ml pyruvate kinase, and 10 pg/ml lactate dehydrogenase (LDH). Solanum Topo4 buffer: 100 mM Tris 7.5, 6 mM MgCl2, 20 mM KCn, 2.5 mM phosphoenolpyruvate, 0_2 mM NADH, 10 mM DTT, 5.25 pg/ml linearized DNA, 50 pg/ml BSA , 30 #g/ml pyruvate, and 10 pg/ml lactate dehydrogenase (LDH). The compounds of the invention were found to inhibit TopoIV. In certain embodiments, the compounds of the invention inhibit TopoIV with a Ki value of less than 50 nM in the assay described above. Example 29 Sensitivity Test in Liquid Medium The antimicrobial activity of the compounds of the present invention was also tested by sensitivity test in liquid medium. These tests are carried out within the guidance of the most recent NCCLS document specifying this practice: "M7-A5 Method for Bacterial Dilution Antimicrobial Sensitivity Testing for Aerobic Growth; Approved Criteria - Fifth Edition (2000)". Other publications such as 'Antibiotics in Laboratory Medicine' (published by V. Lorian, Publishers, William and Wilkins, 1996) provide basic practical techniques for laboratory antibiotic testing. Basically, several discrete bacterial colonies (3 to 7) of S. aureus from a new streak culture m are transferred to a suitably enriched fluid culture medium such as MHB, if appropriate to supplement complex refractory organisms. This growth overnight O:\90\90896.DOC -103- 1334416 The density was then diluted 1 or 2 thousand-fold to produce a culture density of between 5χ1〇5*5χ1〇6 CFU per ml. Alternatively, the new colony can be found at 37. 〇 culture about * to 8 small mites until the culture equals or exceeds 〇 5 standard turbidity (about 1 _5 Χ 1 〇 8 cells per ml) and is diluted to produce the same per liter as above

CFlJ。在一更方便的方法中，使用商品機械裝置（BBL ROMPT提示系統）製備培養物，其包括直接地以棒接觸五 菌落，其底部包含網狀凹槽，接著適當體積的在鹽水中之 細菌的懸浮液。從此細胞懸浮液製備至適當培養細胞密度 之稀釋液。用於測試的流體培養基由補充每升。2,之5〇毫 克和每升25毫克Mg2+之MHB所組成。製造控制組抗生素之 標準稀釋板且以NCCLS標準M7_A5儲存，稀釋範圍典型地 在每宅升128 pg到每毫升〇.015料(藉由2_倍連續稀釋）。為 了實驗在同一天新鮮地溶解及稀釋測試化合物；使用與上 过相同或相似範圍的濃度。測試化合物和控制組分發至多CFlJ. In a more convenient method, the culture is prepared using a commercial mechanical device (BBL ROMPT prompting system) comprising direct contact with five colonies with a rod, the bottom of which contains a reticulated groove, followed by an appropriate volume of bacteria in saline. suspension. A dilution of the cell suspension is prepared from the cell suspension. The fluid medium used for the test was supplemented by liters per liter. 2, 5 gram milligrams and MHB of 25 milligrams of Mg2+ per liter. Standard dilution plates for control group antibiotics were made and stored in NCCLS standard M7_A5, typically ranging from 128 pg per house to 〇.015 per ml (by 2x serial dilution). The test compound was freshly dissolved and diluted on the same day for the experiment; concentrations in the same or similar ranges as above were used. Test compound and control component are issued at most

井盤内和加入測試細菌以使最後培物為每井約5xl04 CFU 和最後體積為1〇〇微升。該等盤在35〇c培養過夜（16到2〇小 時）和以眼睛檢查濁度或以多井盤讀計定量。終點最小抑制 濃度（MIC)為測試微生物（金黃色葡萄球菌）不生長之藥物 的最低漢度。該等測定也與包含在上述二公告之適當表比 較以確定抗菌活性的範圍是在此標準化化驗之可接受範圍 内。 在上述金黃色葡萄球菌MIC化驗中發現本發明化合物具 有抗微生物活性。 而我們已描述本發明之許多具體實施例，顯而易知我們Test bacteria were added to the well plate to give a final pellet of approximately 5 x 1040 CFU per well and a final volume of 1 microliter. The plates were incubated overnight (16 to 2 hrs) at 35 〇c and checked for turbidity by eye or by multi-well plate reading. The endpoint minimum inhibitory concentration (MIC) is the lowest degree of toxicity of the test microorganism (S. aureus). These assays are also compared to the appropriate tables included in the above two publications to determine the extent of antimicrobial activity within the acceptable range for this standardized assay. The compounds of the present invention were found to have antimicrobial activity in the above S. aureus MIC assay. While we have described many specific embodiments of the invention, it is obvious to us that we

〇：V9〇\9〇896.D〇C -104- 1334416 的基本結構可被改變以提供利用本發明的產物和方法之其 他具體貫綠例。 O:\90\90896.DOC -105-The basic structure of 〇:V9〇\9〇896.D〇C-104-1334416 can be altered to provide other specific green examples utilizing the products and methods of the present invention. O:\90\90896.DOC -105-

Claims (1)

13344161334416 第093102200號專利申請案 中文申s青專利範圍替換本(9|^g·月〕 拾、申請專利範圍A 一種式I之化合物：Patent Application No. 093102200 Chinese s green patent replacement form (9|^g·month) Pick up, apply for patent range A A compound of formula I: 或其醫藥上可接受的鹽，其中： w選自氮、CH或CF ; X選自CH或CF ; Z為Ο或NH ; .R1為苯基或具有1-3個獨立選自氧、氮或硫之雜原子的 5-6員雜芳基環，其中： R 被 0-3 個獨立選自-(T)y-Ar、R’ ' 酮基、' C02R’、OR·、n(R')2、SR'、N02、鹵素、CN、C(0)N(R')2、 nr’c(o)r'、so2r’、so2n(r’)2或nr’so2r·之基取代； y為0或1 ; Τ為直鏈或支鏈Cm亞烷基鏈，其中一個τ之亞甲基單位 可視需要選擇性被-ο-、-ΝΗ-或-S-置換； R'各自獨立選自氫、Ci.4脂族或5-6員飽和、不飽和，或 具有0-3個獨立選自氮、氧或硫之雜原子的芳基環，其中： R·被0-3個獨立選自鹵素、酮基、r〇、n(r0)2、〇R0、 CO2R0、NR0C(〇)R0、C(0)N(R0)2、S02R0、S02N(R0)2 或nr°so2r。之基取代，其中： 90896-990623.doc 1334416 R。各自獨立選自氫、Cl·4脂族或5_6員飽和、不飽 和，或具有0-3個獨立選自氮、氧或硫之雜原子的芳 基環，和其中： 二個在R1的相鄰位置上之取代基可一起形成5_7 員飽和、部份不飽和，或具有〇_3個獨立選自氮、 氧或硫之雜原子的芳基環； Ar為苯基，C3·7環烷基，5_6員飽和、具有卜2個獨立選 自氮、氧或硫之雜原子的雜環，或具有丨—2個氮的5_6員雜 芳基環，其中： Ar被0-3個獨立選自R，、酮基、c〇2R·、〇R,、鹵素、 S02R'或C(0)R’之基取代； R2選自氫或（^-3脂族基；和 環A為具有1-3個獨立選自氮、氧或硫之雜原子的5_6員 雜芳基環，其限制條件為該環在鄰近連接環B的點之位置 具有氫鍵受體，其中： 環A被0-3個獨立選自R，、酮基、c〇2R，、〇R,、n(r|)2、 鹵素、CN、C(0)N(R,)2、NR,c(〇)R，、或 nr，s〇2R，之基 取代，及其中： Α 二個在環Α的相鄰位置上之取代基可一起形成6員 飽和的雜環或具有1 -2個氮的雜芳環。 2.如申請專利範圍帛1項之化合物’其中環A係選自下列视 需要選擇性被取代之環： 90896-990623.docOr a pharmaceutically acceptable salt thereof, wherein: w is selected from nitrogen, CH or CF; X is selected from CH or CF; Z is deuterium or NH; R1 is phenyl or has 1-3 independently selected from oxygen, nitrogen Or a 5-6 membered heteroaryl ring of a hetero atom of sulfur, wherein: R is 0-3 independently selected from the group consisting of -(T)y-Ar, R' 'keto, 'C02R', OR·, n(R ')2, SR', N02, halogen, CN, C(0)N(R')2, nr'c(o)r', so2r', so2n(r')2 or nr'so2r· y is 0 or 1; Τ is a linear or branched Cm alkylene chain, wherein a methylene unit of τ can be selectively replaced by -ο-, -ΝΗ- or -S-; R' is independent An aryl ring selected from the group consisting of hydrogen, Ci.4 aliphatic or 5-6 member saturated, unsaturated, or having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein: R· is 0-3 Independently selected from halogen, keto, r, n(r0)2, 〇R0, CO2R0, NR0C(〇)R0, C(0)N(R0)2, S02R0, S02N(R0)2 or nr°so2r. Substituted by, wherein: 90896-990623.doc 1334416 R. Each is independently selected from the group consisting of hydrogen, Cl.4 aliphatic or 5-6 member saturated, unsaturated, or an aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein: two phases in R1 The substituents at the adjacent positions may together form a 5-7-membered saturated, partially unsaturated, or aryl ring having 〇3 heteroatoms independently selected from nitrogen, oxygen or sulfur; Ar is a phenyl group, C3·7 naphthenic ring a heterocyclic ring having 5 to 6 members saturated, having 2 hetero atoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered heteroaryl ring having 2 to 2 nitrogens, wherein: Ar is independently selected from 0 to 3 Substituted from R, keto, c〇2R·, 〇R, halogen, S02R' or C(0)R'; R2 is selected from hydrogen or (^-3 aliphatic; and ring A is 1 a 3-6 membered heteroaryl ring independently selected from heteroatoms of nitrogen, oxygen or sulfur, with the proviso that the ring has a hydrogen bond acceptor at a position adjacent to the point of attachment ring B, wherein: ring A is 0- 3 independently selected from R, keto, c〇2R, 〇R, n(r|)2, halogen, CN, C(0)N(R,)2, NR, c(〇)R, Or nr, s〇2R, the base substitution, and wherein: 二个 two adjacent positions in the ring The substituents may together form a 6-membered saturated heterocyclic ring or a heteroaryl ring having 1 to 2 nitrogens. 2. The compound of claim 1 wherein the ring A is selected from the following ring optionally substituted as desired : 90896-990623.doc 13344161334416 y z aa bb o 3 .如申請專利範圍第2項之化合物，其中環A為選自環a、f s、w、y或z的視需要選擇性被取代之環： D JOy z aa bb o 3 . A compound according to claim 2, wherein ring A is a ring optionally substituted with a ring selected from the ring a, f s, w, y or z: D JO 或 z a f 1 s w y 4. 如申請專利範圍第1項之化合物，其中： R1選自視需要選擇性被取代之苯基或具有1-2個氮之 5-6員雜芳基環。 5. 如申請專利範圍第4項之化合物，其中R1為選自吡啶-2-基、p比咬-3-基、p比淀-4-基、嘲淀-2-基、嘴咬-4-基、嘲咬 90896-990623.doc 1334416 _5·基、嘧啶_6_基、咪唑基、咪唑_2基、咪唑_4_基或 米坐5 -基的視需要選擇性被取代之環。 6·如申清專利範圍第5項之化合物，Ri被〇_2個獨立選自鹵 素、嗣基、R'、C〇2r·、ORi、n(Ri)2、SR.、c⑼N(R，）2、 NRC(0)R’、S〇2R’、S02N(R，）2或NR，S02R，之基取代。 7.如申請專利範圍第6項之化合物，R2選自甲基、乙基、異 丙基或環丙基。Or z a f 1 s w y 4. A compound according to claim 1, wherein: R1 is selected from a phenyl group optionally substituted with phenyl or a 5-6 membered heteroaryl ring having 1-2 nitrogen. 5. A compound according to claim 4, wherein R1 is selected from the group consisting of pyridin-2-yl, p-but-3-yl, p-pre--4-yl, mock-2-yl, mouth bit-4 - A base, a singularity of 90896-990623.doc 1334416 _5·yl, pyrimidine -6-yl, imidazolyl, imidazolyl-2-yl, imidazolyl-4-yl or a cyclo-substituent optionally substituted ring. 6. According to the compound of the fifth paragraph of the patent scope, Ri is 〇_2 independently selected from halogen, sulfhydryl, R', C〇2r·, ORi, n(Ri)2, SR., c(9)N(R, 2, NRC (0) R', S 〇 2R ', S02N (R,) 2 or NR, S02R, the base substitution. 7. A compound of claim 6 wherein R2 is selected from the group consisting of methyl, ethyl, isopropyl or cyclopropyl. 8.如申請專利範圍第1項之化合物，其中該化合物為式II_a R\ -°8. The compound of claim 1, wherein the compound is of formula II_a R\-° II-a 或其醫藥上可接受的鹽。II-a or a pharmaceutically acceptable salt thereof. 其中該化合物為式ΠΙ : 9.如申请專利範圍第1項之化合物， ΰ ηWherein the compound is of the formula: 9. The compound of claim 1 is ΰ η Ζ&gt;〇 R2 III 或其醫藥上可接受的鹽，其中： 90896-990623.doc -4- 1334416 所述之P比咬g同環被〇_2個獨立選自齒素、_基、R'、 C02R’、OR’、N(R')2、SR’、C(0)N(R，)2、NR’C(0)R·、s〇2R，、 S02N(R')2或NR'S02R，之基取代。Ζ&gt;〇R2 III or a pharmaceutically acceptable salt thereof, wherein: 90896-990623.doc -4- 1334416 is described as having a P-biting g-like ring 〇_2 independently selected from dentate, _ group, R' , C02R', OR', N(R')2, SR', C(0)N(R,)2, NR'C(0)R·, s〇2R, S02N(R')2 or NR 'S02R, the base is replaced. 10_如申請專利範圍第9項之化合物，其中該化合物為式m_a: &gt;0 或其醫藥上可接受的鹽。 11.如申請專利範圍第10項之化合物，其中： R'為氫或CN4脂族，和其中： R'視需要選擇性被苯基或吡啶基取代。10_ The compound of claim 9, wherein the compound is of the formula m_a: &gt; 0 or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 10, wherein: R' is hydrogen or a CN4 aliphatic group, and wherein: R' is optionally substituted with a phenyl or pyridyl group. 1 2.如申請專利範圍第1項之化合物，其中該化合物為式IV : 或其醫藥上可接受的鹽 13·如申請專利範圍第12項之化合物，其中Ar為視需要選擇 90896-990623.doc 明 4416 性被取代之具有1-2個獨立選自篇卜i 。 曰孔、亂或硫的雜原子之5_6 員飽和環。 如申請專利範圍第u項之化合 物其中Ar為視需要選擇 性破取代之具有卜2個氮、％員之雜芳基環。 15·如申請專利範圍第12項之化合物， ，、Υ ΑΓ马視需要選摆 性被取代之具有1-2個氮的6·員雜芳基環。 评 16·如申請專利範圍第12項之化合物，盆^ 性被取代之苯基。 ，、中^為視需要選擇 R如申請專利範圍第i項之》合物，其中該化合物為式^1 2. The compound of claim 1, wherein the compound is Formula IV: or a pharmaceutically acceptable salt thereof. 13. The compound of claim 12, wherein Ar is selected 90896-990623 as needed. Doc Ming 4416 is replaced by 1-2 independent from the article i. A 5-6-membered saturated ring of a hetero atom of a pupil, disorder, or sulfur. For example, in the compound of the scope of the patent application, in which Ar is a heteroaryl ring having two nitrogen and a member, which is optionally substituted. 15. If the compound of claim 12 is applied, the 6 ΑΓ ΑΓ ΑΓ 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 。 。 。 。 。 。 。 。 。 。 。 。 。 Comment 16·If the compound of claim 12 is a compound, the phenyl group is substituted. , , and ^ are selected as needed. R is the compound of the i-th patent of the patent application, wherein the compound is of the formula ^ V 或其醫藥上可接受的鹽 18.如申請專利範圍第17項^合物，其中該化合物為式W :V or a pharmaceutically acceptable salt thereof. 18. The compound of claim 17 wherein the compound is of formula W: VI .山一 0 或其醫藥上可接受的鹽。 其中R2為 19·如申請專利範圍第8、11、12或17項之化合物 90896-990623.doc 1334416 乙基。 20. —種選自由下列所組成之群組之化合物：VI. Hill-1 or its pharmaceutically acceptable salt. Wherein R2 is 19. The compound of claim 8, paragraph 8, 8, 12 or 17 of the patent application 90896-990623.doc 1334416 ethyl. 20. A compound selected from the group consisting of: A PA P 90896-990623.doc90896-990623.doc 13344161334416 1-17 Μ 81-17 Μ 8 1-19 1-201-19 1-20 1-211-21 1-22 1-23 1-24 、〇1-22 1-23 1-24, 〇 1-25 1-26 1-281-25 1-26 1-28 1-30 1-31 1-32 1-291-30 1-31 1-32 1-29 1-35 90896-990623.doc1-35 90896-990623.doc 13344161334416 1-45 1-46 1-47 1-481-45 1-46 1-47 1-48 1-49 1-50 1-51 1-521-49 1-50 1-51 1-52 90896-990623.doc -9- 133441690896-990623.doc -9- 1334416 1-57 1-60 1-61 1-621-57 1-60 1-61 1-62 1-63 1-64 1-65 1-661-63 1-64 1-65 1-66 1-70 1-67 1-68 1-69 90896-990623.doc •10- 13344161-70 1-67 1-68 1-69 90896-990623.doc •10- 1334416 1-76 1-77 1-781-76 1-77 1-78 1-75 OH1-75 OH 1-791-79 1-85 1-861-85 1-86 1-83 1-84 90896-990623.doc -11 - 13344161-83 1-84 90896-990623.doc -11 - 1334416 1-87 1-88 1-89 1-901-87 1-88 1-89 1-90 -NH-NH -NH-NH 〇 V-NH N=a/ 〇 V-NH N. 1-91 1-92 1-93 1-94〇 V-NH N=a/ 〇 V-NH N. 1-91 1-92 1-93 1-94 -NH 1-95 1-96 1-97 、〇 、〇 N^N Λ | 〇丫 N、 v y v λ ^ Λ Λ ΝΓΤΊΓν°Ν nV yL Jljr V上NH 〇卜 &gt;—NH NH )—NH -NH 1-98-NH 1-95 1-96 1-97 , 〇, 〇 N^N Λ | 〇丫N, vyv λ ^ Λ Λ ΝΓΤΊΓν°Ν nV yL Jljr V on NH & & > - NH NH ) - NH - NH 1-98 1-102 1-99 1-100 1-101 90896-990623.doc 12 13344161-102 1-99 1-100 1-101 90896-990623.doc 12 1334416 I-lll 1-112 1-113 1-114I-lll 1-112 1-113 1-114 1-115 1-116 1-117 1-118 90896-990623.doc -13- 1334416 -NH1-115 1-116 1-117 1-118 90896-990623.doc -13- 1334416 -NH 1-1191-119 1-1201-120 1-123 1-124 1-1211-123 1-124 1-121 1-1221-122 1-1261-126 1-1271-127 厂plant 90896-990623.doc 14- 133441690896-990623.doc 14- 1334416 1-135 1-136 1-137 1-1381-135 1-136 1-137 1-138 1-1391-139 1-140 1-141 1-1421-140 1-141 1-142 1-143 1-144 1-145 1-1461-143 1-144 1-145 1-146 90896-990623.doc -15- 133441690896-990623.doc -15- 1334416 1-160 1-1591-160 1-159 HN厂0人。 1-163HN factory 0 people. 1-163 1-165 1-1611-165 1-161 厂 1-162Factory 1-162 1-166 90896-990623.doc -16- Cs) 13344161-166 90896-990623.doc -16- Cs) 1334416 1-171 1-172 1-173 1-1741-171 1-172 1-173 1-174 1-175 1-176 1-177 1-1781-175 1-176 1-177 1-178 1-179 1-180 1-181 1-182 90896-990623.doc -17- 13344161-179 1-180 1-181 1-182 90896-990623.doc -17- 1334416 1-183 1-184 1-185 1-1861-183 1-184 1-185 1-186 1-187 1-188 1-189 1-1901-187 1-188 1-189 1-190 1-191 1-192 1-193 1-1941-191 1-192 1-193 1-194 90896-990623.doc -18- 133441690896-990623.doc -18- 1334416 1-199 1-200 1-201 1-2021-199 1-200 1-201 1-202 1-203 1-204 1-2061-203 1-204 1-206 nh2Nh2 1-205 N1-205 N Cr°Cr° 1-210 1-207 1-208 1-2091-210 1-207 1-208 1-209 1-211 ο1-211 ο οο ΟΟ 1-212 1-213 1-214 90896-990623.doc -19- 13344161-212 1-213 1-214 90896-990623.doc -19- 1334416 1-219 1-220 1-221 1-2221-219 1-220 1-221 1-222 1-223 1-224 1-225 1-2261-223 1-224 1-225 1-226 1-227 1-228 1-229 1-230 90896-990623.doc 20- V 13344161-227 1-228 1-229 1-230 90896-990623.doc 20- V 1334416 1-231 1-232 1-233 1-2341-231 1-232 1-233 1-234 1-243 1-244 1-245 1-246 90896-990623.doc •21 · 13344161-243 1-244 1-245 1-246 90896-990623.doc •21 · 1334416 1-247 1-248 1-2491-247 1-248 1-249 1-2501-250 1-2511-251 1-252 1-253 1-2541-252 1-253 1-254 1-2551-255 1-2581-258 1-259 1-260 1-261 1-262 90896-990623.doc -22- 13344161-259 1-260 1-261 1-262 90896-990623.doc -22- 1334416 1-263 1-264 1-265 1-2661-263 1-264 1-265 1-266 1-271 1-272 1-273 1-2741-271 1-272 1-273 1-274 1-275 1-276 1-277 1-278 90896-990623.doc -23- 13344161-275 1-276 1-277 1-278 90896-990623.doc -23- 1334416 1-290 1-287 1-2881-290 1-287 1-288 1-291 1-292 1-2891-291 1-292 1-289 1-294 90896-990623.doc -24- 丄丄亡)1-294 90896-990623.doc -24- 丄丄) 21. 22. 23. 24, 25. 26. 1種抑制生物樣品或病患的促旋酶活性之醫藥組合物， ’、包含如申請專利11圍第1項之化合4勿，和醫藥上可接受 的載體、佐劑或媒液。 種抑制生物樣品或病患的τ〇ρ〇 Iv活性之醫藥組合物， 其包含如申請專利範圍第1項之化合物，和醫藥上可接受 的載體、佐劑或媒液。 種抑制生物樣品或病患的促旋酶和τορο IV活性之醫藥 組合物，其包含如申請專利範圍第1項之化合物，和醫藥 上可接受的載體、佐劑或媒液。 種減少病患細菌量之醫藥組合物，其包含如申請專利 範圍第1項之化合物，和醫藥上可接受的载體、佐劑或媒 液。 一種用於治療、預防病患的細菌感染或減少細菌感染之 嚴重性之醫藥組合物，其包含如申請專利範圍第丨項之化 合物’和醫藥上可接受的載體、佐劑或媒液。 如申請專利範圍第25項之醫藥組合物，其中欲治療之細 菌感染以存在下列之一或多項為特徵：肺炎雙球菌 (streptococcus pneumoniae)、釀膿鏈球菌（strept〇c〇ceus 90896-990623.doc -25- 1334416 pyogenes)、糞腸球菌（Enterococcus faecalis)、腸球菌 (Enterococcus faecium)、克雷白氏肺炎桿菌（Klebsiella pneumoniae )、腸細菌屬（Enterobacter sps.)、變形桿菌屬 (Proteus sps.)、綠膿桿菌、大桿腸菌、黏質沙雷氏菌 (Serratia marcesens)、金黃色葡萄球菌、Coag. Neg. Staph、流感嗜血桿菌（Haemophilus inHuenzae)、炭疽桿 菌（Bacillus anthracis)、肺炎黴漿菌（Mycoplasma pneumoniae)、莫拉斯氏菌屬（Moraxella catarralis)、肺炎 披衣菌（Chlamydia pneumoniae)、嗜肺性退伍軍人桿菌 (Legionella pneumophila)、表皮葡萄 ϊ衣菌（Staphylococcus epidermidis)、結核分枝桿菌（Mycobacterium tuberculosis) 或 Helcoibacter pylori ° 2 7.如申請專利範圍第2 6項之醫藥組合物，其中欲治療之細 菌感染係選自下列之一或多項：尿道感染、呼吸器官感 染、肺炎、前列腺炎、皮膚或軟組織感染、腹内感染、 血流感染或熱性嗜中性白血球減少（neutropenic)病人的 感染。 28. 如申請專利範圍第27項之醫藥組合物，其尚包含額外治 療劑，為與該化合物之多劑型的部份或為分開劑型。 29. 如申請專利範圍第26項之醫藥組合物，其進一步包含增 加細菌生物對抗生素之敏感性的藥劑。 30. 如申請專利範圍第21-25項中任一項之醫藥組合物，其額 外地包含一種選自抗生素、抗發炎劑、基質金屬蛋白酶 抑制劑、脂肪氧合酶抑制劑、細胞激素拮抗劑、免疫抑 90896-990623.doc -26- 1334416 制劑、抗癌劑、抗病毒劑、細胞激素、生長因子、免疫 調節劑、前列腺素、抗血管增生化合物或增加細菌生物 對抗生素的敏感性之藥劑的額外治療劑。 90896-990623.doc 27-21. 22. 23. 24, 25. 26. A pharmaceutical composition for inhibiting the gyrase activity of a biological sample or a patient, ', including the compound 4 of the first paragraph of claim 11 and the pharmaceutical Accepted carrier, adjuvant or vehicle. A pharmaceutical composition for inhibiting τ〇ρ〇 Iv activity of a biological sample or a patient, which comprises a compound as claimed in claim 1, and a pharmaceutically acceptable carrier, adjuvant or vehicle. A pharmaceutical composition for inhibiting the activity of gyrase and τορο IV of a biological sample or a patient, which comprises a compound as claimed in claim 1, and a pharmaceutically acceptable carrier, adjuvant or vehicle. A pharmaceutical composition for reducing the amount of bacteria in a patient, which comprises a compound as in claim 1 of the patent application, and a pharmaceutically acceptable carrier, adjuvant or vehicle. A pharmaceutical composition for treating or preventing a bacterial infection of a patient or reducing the severity of a bacterial infection, comprising a compound as claimed in the scope of the patent application and a pharmaceutically acceptable carrier, adjuvant or vehicle. A pharmaceutical composition according to claim 25, wherein the bacterial infection to be treated is characterized by the presence of one or more of the following: Streptococcus pneumoniae, Streptococcus pyogenes (strept〇c〇ceus 90896-990623. Doc -25- 1334416 pyogenes), Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps., Proteus sps. ), Pseudomonas aeruginosa, S. cerevisiae, Serratia marcesens, Staphylococcus aureus, Coag. Neg. Staph, Haemophilus inHuenzae, Bacillus anthracis, pneumonia Mycoplasma pneumoniae, Moraxella catarralis, Chlamydia pneumoniae, Legionella pneumophila, Staphylococcus epidermidis, tuberculosis Mycobacterium tuberculosis or Helcoibacter pylori ° 2 7. As claimed in Article 26 A pharmaceutical composition wherein the bacterial infection to be treated is selected from one or more of the following: urinary tract infection, respiratory infection, pneumonia, prostatitis, skin or soft tissue infection, intra-abdominal infection, bloodstream infection or thermal neutropenia (neutropenic) infection of the patient. 28. The pharmaceutical composition of claim 27, which further comprises an additional therapeutic agent, either as part of a multi-dose form of the compound or as a separate dosage form. 29. The pharmaceutical composition of claim 26, further comprising an agent that increases the sensitivity of the bacterial organism to antibiotics. The pharmaceutical composition according to any one of claims 21 to 25, which additionally comprises an antibiotic, an anti-inflammatory agent, a matrix metalloproteinase inhibitor, a lipoxygenase inhibitor, a cytokine antagonist , immunosuppression 90896-990623.doc -26- 1334416 Formulations, anticancer agents, antiviral agents, cytokines, growth factors, immunomodulators, prostaglandins, anti-angiogenic compounds or agents that increase the sensitivity of bacterial organisms to antibiotics Extra therapeutic agent. 90896-990623.doc 27-
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI595002B (en) * 2012-07-18 2017-08-11 思沛羅三南公司 Solid forms of (r)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1h-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl dihydrogen phosphate and salts thereof

Families Citing this family (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1511482B1 (en) * 2002-06-13 2006-11-15 Vertex Pharmaceuticals Incorporated 2-ureido-6-heteroaryl-3h-benzoimidazole-4-carboxylic acid derivatives and related compounds as gyrase and/or topoisomerase iv inhibitors for the treatment of bacterial infections
US8193352B2 (en) 2003-01-31 2012-06-05 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
US8404852B2 (en) 2003-01-31 2013-03-26 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
AR042956A1 (en) * 2003-01-31 2005-07-13 Vertex Pharma GIRASA INHIBITORS AND USES OF THE SAME
US7569591B2 (en) * 2003-01-31 2009-08-04 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
US7618974B2 (en) 2003-01-31 2009-11-17 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
US7582641B2 (en) * 2003-01-31 2009-09-01 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
US7863335B2 (en) * 2004-07-23 2011-01-04 The University Of Medicine And Dentistry Of New Jersey Non-antibiotic intervention of chlamydial infection
MX2007014114A (en) 2005-05-10 2008-03-14 Intermune Inc Pyridone derivatives for modulating stress-activated protein kinase system.
DE102005028862A1 (en) * 2005-06-22 2007-01-11 Sanofi-Aventis Deutschland Gmbh Substituted heterocycles, their use as medicament and pharmaceutical compositions containing them
EP1948635A1 (en) * 2005-11-07 2008-07-30 Vertex Pharmaceuticals Incorporated Benzimidazole derivatives as gyrase inhibitors
GB0612428D0 (en) * 2006-06-22 2006-08-02 Prolysis Ltd Antibacterial agents
US8481544B2 (en) 2006-06-22 2013-07-09 Biota Europe Limited Antibacterial compositions
GB0724349D0 (en) * 2007-12-13 2008-01-30 Prolysis Ltd Antibacterial agents
WO2009001915A1 (en) * 2007-06-28 2008-12-31 Takeda Pharmaceutical Company Limited Substituted imidazole compound and use thereof
WO2009027733A1 (en) * 2007-08-24 2009-03-05 Astrazeneca Ab (2-pyridin-3-ylimidazo[1,2-b]pyridazin-6-yl) urea derivatives as antibacterial agents
US8217172B2 (en) * 2007-12-07 2012-07-10 Vertex Pharmaceuticals Incorporated Solid forms of 1-ethyl-3-(5-(5-fluoropyridin-3-yl)-7-(pyrimidin-2-yl)-1H-benzo[d]imidazol-2-yl)urea
GB0724342D0 (en) 2007-12-13 2008-01-30 Prolysis Ltd Anitbacterial compositions
US7820665B2 (en) * 2007-12-19 2010-10-26 Amgen Inc. Imidazopyridazine inhibitors of PI3 kinase for cancer treatment
TW200940537A (en) * 2008-02-26 2009-10-01 Astrazeneca Ab Heterocyclic urea derivatives and methods of use thereof
JP5627574B2 (en) 2008-06-03 2014-11-19 インターミューン， インコーポレイテッド Compounds and methods for treating inflammatory and fibrotic diseases
AU2009254930A1 (en) 2008-06-04 2009-12-10 Astrazeneca Ab Heterocyclic urea derivatives for the treatment of bacterial infections
WO2009156966A1 (en) * 2008-06-25 2009-12-30 Ranbaxy Laboratories Limited Benzothiazoles and aza-analogues thereof use as antibacterial agents
EP2626072B1 (en) * 2009-04-02 2019-12-04 Merck Patent GmbH Piperidine and piperazine derivatives as autotaxin inhibitors
WO2011028492A2 (en) * 2009-08-24 2011-03-10 The Regents Of The University Of California Sortase a inhibitors
US20110120915A1 (en) * 2009-11-24 2011-05-26 Chevron U.S.A. Inc. Hydrogenation of solid carbonaceous materials using mixed catalysts
AR081331A1 (en) * 2010-04-23 2012-08-08 Cytokinetics Inc AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME
AR081626A1 (en) 2010-04-23 2012-10-10 Cytokinetics Inc AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS
EP2560488B1 (en) 2010-04-23 2015-10-28 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US20150174137A1 (en) * 2010-06-02 2015-06-25 Alcon Research, Ltd. Compositions for treating microbial infections
SG191945A1 (en) * 2011-01-14 2013-08-30 Vertex Pharma Process of making gyrase and topoisomerase iv inhibitors
AU2012205415B2 (en) * 2011-01-14 2017-02-02 Spero Therapeutics, Inc. Pyrimidine gyrase and topoisomerase IV inhibitors
CA2824403C (en) * 2011-01-14 2019-09-24 Vertex Pharmaceuticals Incorporated Solid forms of gyrase inhibitor (r)-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-(tetrahydrofuran-2-yl)-1h-benzimidazol-2-yl]urea
WO2012097270A1 (en) * 2011-01-14 2012-07-19 Vertex Pharmaceuticals Incorporated Solid forms of gyrase inhibitor (r)-1-ethyl-3-[5-[2-{1-hydroxy-1-methyl-ethyl}pyrimidin-5-yl]-7-(tetrahydrofuran-2-yl}-1h-benzimidazol-2-yl]urea
ES2576298T3 (en) 2011-06-20 2016-07-06 Vertex Pharmaceuticals Incorporated Phosphate esters of gyrase and topoisomerase inhibitors
US9572809B2 (en) 2012-07-18 2017-02-21 Spero Trinem, Inc. Combination therapy to treat Mycobacterium diseases
AR092742A1 (en) 2012-10-02 2015-04-29 Intermune Inc ANTIFIBROTIC PYRIDINONES
NZ714669A (en) 2013-06-21 2021-07-30 Zenith Epigenetics Ltd Novel bicyclic bromodomain inhibitors
JP6599852B2 (en) 2013-06-21 2019-10-30 ゼニス・エピジェネティクス・リミテッド Novel substituted bicyclic compounds as bromodomain inhibitors
AU2014298051B2 (en) 2013-07-31 2018-11-15 Zenith Epigenetics Ltd. Novel quinazolinones as bromodomain inhibitors
KR20160115986A (en) 2014-02-03 2016-10-06 스페로 자이레이스, 인크 Antibacterial combination comprising polymyxin
EP2913330A1 (en) * 2014-02-27 2015-09-02 Laboratoire Biodim Condensed derivatives of imidazole useful as pharmaceuticals
JP6525437B2 (en) 2014-04-02 2019-06-05 インターミューン， インコーポレイテッド Antifibrotic pyridinone
WO2016087936A1 (en) 2014-12-01 2016-06-09 Zenith Epigenetics Corp. Substituted pyridinones as bromodomain inhibitors
CN107207474B (en) 2014-12-11 2021-05-07 恒翼生物医药科技(上海)有限公司 Substituted heterocycles as bromodomain inhibitors
EP3233846A4 (en) 2014-12-17 2018-07-18 Zenith Epigenetics Ltd. Inhibitors of bromodomains
CN105884752B (en) * 2015-02-13 2018-08-31 山东轩竹医药科技有限公司 And ring class gyrase and topoisomerase I V inhibitor
US10562886B2 (en) 2015-05-21 2020-02-18 The Regents Of The University Of California Anti-cancer compounds
CN106167486B (en) * 2015-05-22 2019-06-14 北京四环制药有限公司 Monocycle class gyrase and topoisomerase I V inhibitor
ES2914681T3 (en) 2015-07-02 2022-06-15 Janssen Sciences Ireland Unlimited Co antibacterial compounds
CA3026010A1 (en) 2016-06-16 2017-12-21 Janssen Sciences Ireland Unlimited Company Heterocyclic compounds as antibacterials
AU2017280334C1 (en) 2016-06-24 2022-10-20 AtlasMedx, Inc Phthalazine derivatives as inhibitors of PARP1, PARP2 and/or tubulin useful for the treatment of cancer
MA47676A (en) 2017-03-01 2021-06-02 Janssen Sciences Ireland Unlimited Co POLYTHERAPY
RU2019133662A (en) 2017-03-24 2021-04-26 Тайсо Фармасьютикал Ко., Лтд. DERIVATIVE OF 2 (1H) -QUINOLINONE
CN110801455B (en) * 2019-11-12 2020-06-02 河北医科大学第二医院 Pharmaceutical composition for treating MRSA and application thereof
EP4077310B1 (en) * 2019-12-19 2024-05-01 Université de Strasbourg Sigma-1 receptor ligands and uses thereof
KR20230169573A (en) * 2022-06-09 2023-12-18 한국화학연구원 Benzimidazole derivatives, preparation method thereof, and pharmaceutical composition for the prevention or treatment of cancer or infectious diseases containing the same as an active ingredient

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2015676A1 (en) * 1970-04-02 1971-10-21 Farbenfabriken Bayer Ag, 5090 Leverkusen New imines of 2-formyl-quinoxalinedi-N-oxide carbonic acid- (3) and their salts, processes for their preparation and their use as antimicrobial agents
US4174400A (en) 1978-09-13 1979-11-13 Merck & Co., Inc. Anthelmintic benzimidazoles
US4512998A (en) 1980-10-20 1985-04-23 Schering Corporation Anthelmintic benzimidazole carbamates
CA2028530A1 (en) 1989-11-21 1991-05-22 Christian Hubschwerlen Substituted pyrimidobenzimidazole derivatives
EP0534363B1 (en) * 1991-09-27 1997-07-09 Merrell Pharmaceuticals Inc. Novel 2-substituted indane-2-mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
DE19514313A1 (en) 1994-08-03 1996-02-08 Bayer Ag Benzoxazolyl- and Benzothiazolyloxazolidinone
HRP960159A2 (en) 1995-04-21 1997-08-31 Bayer Ag Benzocyclopentane oxazolidinones containing heteroatoms
US5643935A (en) 1995-06-07 1997-07-01 The University Of North Carolina At Chapel Hill Method of combatting infectious diseases using dicationic bis-benzimidazoles
TW538046B (en) 1998-01-08 2003-06-21 Hoechst Marion Roussel Inc Aromatic amides having antiobiotic activities and the preparation processes, intermediates and pharmaceutical composition thereof
AUPP873799A0 (en) 1999-02-17 1999-03-11 Fujisawa Pharmaceutical Co., Ltd. Pyridine compounds
GB9911594D0 (en) 1999-05-19 1999-07-21 Smithkline Beecham Plc Novel compounds
GB9912413D0 (en) 1999-05-28 1999-07-28 Pfizer Ltd Compounds useful in therapy
SI1341769T1 (en) * 2000-12-15 2008-02-29 Vertex Pharma Bacterial gyrase inhibitors and uses thereof
EP1511482B1 (en) 2002-06-13 2006-11-15 Vertex Pharmaceuticals Incorporated 2-ureido-6-heteroaryl-3h-benzoimidazole-4-carboxylic acid derivatives and related compounds as gyrase and/or topoisomerase iv inhibitors for the treatment of bacterial infections
US7582641B2 (en) 2003-01-31 2009-09-01 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
US7569591B2 (en) 2003-01-31 2009-08-04 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
AR042956A1 (en) * 2003-01-31 2005-07-13 Vertex Pharma GIRASA INHIBITORS AND USES OF THE SAME
US7618974B2 (en) * 2003-01-31 2009-11-17 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
US8193352B2 (en) 2003-01-31 2012-06-05 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
EP1948635A1 (en) 2005-11-07 2008-07-30 Vertex Pharmaceuticals Incorporated Benzimidazole derivatives as gyrase inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI595002B (en) * 2012-07-18 2017-08-11 思沛羅三南公司 Solid forms of (r)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1h-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl dihydrogen phosphate and salts thereof

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